Drug Discovery by Design

7/26/2019 Drug Discovery by Design

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Drug Discovery by DesignDrug Discovery by DesignGareth ThomasGareth Thomas


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2.1. Introduction2.1. Introduction

Drug discovery isDrug discovery is part luck and part structuredpart luck and part structuredinvestigationinvestigation..

At the beginning of the nineteenth century it wasAt the beginning of the nineteenth century it was

largely carried out by individuals but it nowlargely carried out by individuals but it nowrequires teamwork, the members of the teamrequires teamwork, the members of the teambeingbeing specialists in various fieldsspecialists in various fields, such as, such asmedicine, biochemistry, chemistry, computerisedmedicine, biochemistry, chemistry, computerised

molecular modelling, pharmaceutics,molecular modelling, pharmaceutics,pharmacology, microbiology, toicology, physiologypharmacology, microbiology, toicology, physiologyand pathology.and pathology.


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04/12/1604/12/16 prof. azaprof. aza 33

lead compoundslead compounds

!he drugs used in medicine are!he drugs used in medicine aredeveloped from so"calleddeveloped from so"called leadleadcompoundscompounds#$igure 2.1%.#$igure 2.1%.

!hese compounds were originally!hese compounds were originallydiscovered by investigating localdiscovered by investigating localfolk remedies, and natural productsfolk remedies, and natural products

such as plants #land and marine%,such as plants #land and marine%,trees, microorganisms and animals.trees, microorganisms and animals.


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!hese are still useful sources of lead!hese are still useful sources of leadcompounds but many are now producedcompounds but many are now producedas a result of investigations into theas a result of investigations into thenature of disease statesnature of disease states..

&ead compounds are often unsuitable&ead compounds are often unsuitablefor clinical use because theyfor clinical use because they may bemay beeither too toic or have seriouseither too toic or have seriousunwanted side effects.unwanted side effects.

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'owever, their structures ser'owever, their structures serveveas theas thestarting points for the synthesisstarting points for the synthesis of so"of so"called analogues, one or more of whichcalled analogues, one or more of whichmay be suitable for clinical use #$iguremay be suitable for clinical use #$igure2.1%.2.1%.

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04/12/1604/12/16 prof. azaprof. aza 77

The approach to drug designThe approach to drug design

!he approach to drug design!he approach to drug designdepends ondepends onthe ob(ectives of the design team.the ob(ectives of the design team.!hese ob(ectives can range from!hese ob(ectives can range from

changing the pharmacokinetics of anchanging the pharmacokinetics of aneisting drug to designing a completelyeisting drug to designing a completelynew compound.new compound.

In all cases the team will start byIn all cases the team will start by

devising an outline of the intendeddevising an outline of the intendedinvestigationinvestigation..


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$or eample, if the ob(ective is$or eample, if the ob(ective is totomodify themodify thepharmacokineticspharmacokinetics of anof aneisting drug the design team has toeisting drug the design team has todecide what structural modificationsdecide what structural modificationsneed to be investigated in order toneed to be investigated in order toachieve that ob(ective.achieve that ob(ective.

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)n the other hand, if the ob(ective is to)n the other hand, if the ob(ective is tofind a new drug for a specific medicalfind a new drug for a specific medical

problem the starting point is aproblem the starting point is aknowledge of the biochemistryknowledge of the biochemistryof theof thecondition and*or the microorganismcondition and*or the microorganismresponsible for the condition.responsible for the condition.

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!his may require basic research into the!his may require basic research into thedisease"causing processdisease"causing process before initiating thebefore initiating thedrug design investigation #$igure 2.1%. !hedrug design investigation #$igure 2.1%. !heinformation obtained is used by the team toinformation obtained is used by the team todecide where intervention would be mostdecide where intervention would be mostlikely to bring about the desired result.likely to bring about the desired result.

)nce the point of intervention has been)nce the point of intervention has beenselected the team hasselected the team has to decide on theto decide on the

structure of a lead compound that couldstructure of a lead compound that couldpossibly bring about the required changepossibly bring about the required change..


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Objectie !r"# $isi#%Objectie !r"# $isi#%

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A number of candidates are usuallyA number of candidates are usuallyconsidered but the epense ofconsidered but the epense ofproducing drugs dictates that the teamproducing drugs dictates that the team

hashas to choose only one or two of theseto choose only one or two of thesecompoundscompounds to either act as the lead orto either act as the lead ortoto bbe the inspiration for the leade the inspiration for the leadcompound.compound.

!he final selection depends on the!he final selection depends on theeperience of the team.eperience of the team.

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)ne approach to lead compound selection is to)ne approach to lead compound selection is tocarry out a comprehensive literature andcarry out a comprehensive literature anddatabase search to identify compounds founddatabase search to identify compounds found

in the organismin the organism #endogenous compounds%#endogenous compounds%andandcompounds that are not found in the organismcompounds that are not found in the organism#eogenous compounds%#eogenous compounds% that have somethat have somebiological effect at the intervention site.biological effect at the intervention site.

!hese compounds are used as leads and!hese compounds are used as leads andmodified in an appropriate manner.modified in an appropriate manner.


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&ea$ 'ompo"%$ se(ectio%&ea$ 'ompo"%$ se(ectio%

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)i#"re 2.1. The #e%era( steps i% the $esi#%

of a %e* $r"#.


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+odern approaches to lead compound+odern approaches to lead compounddiscovery includediscovery include combinatorialcombinatorialchemistry and computer modelingchemistry and computer modelingtechniquestechniques ..

!he former uses a simultaneous multiple!he former uses a simultaneous multiplesynthesis technique to produce largesynthesis technique to produce largenumbers of potential leads. !hesenumbers of potential leads. !hesepotential leads are sub(ected to rapidpotential leads are sub(ected to rapid

high"throughput biological screening tohigh"throughput biological screening toidentify the most active leadidentify the most active leadcompounds.compounds.


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)nce identified, these lead compounds are)nce identified, these lead compounds aresub(ect to further development.sub(ect to further development.

omputer modeling is normally usedomputer modeling is normally used to checkto check

whether the three"dimensional structure ofwhether the three"dimensional structure ofthe proposed lead is complementary to thatthe proposed lead is complementary to thatof its receptor domain.of its receptor domain.

'owever, this does require a detailed'owever, this does require a detailedknowledge of the three"dimensionalknowledge of the three"dimensionalstructures of the ligand and target site.structures of the ligand and target site.

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04/12/1604/12/16 prof. azaprof. aza 1818

enantiomers and their racematesenantiomers and their racemates

A ma(or consideration in the selectionA ma(or consideration in the selectionof a lead is its stereochemistry. It isof a lead is its stereochemistry. It isnow recognised that the biologicalnow recognised that the biological

activities of the individualactivities of the individual enantiomersenantiomersand their racematesand their racematesmay be verymay be verydifferent.different.

onsequently, it is necessary to evaluateonsequently, it is necessary to evaluate

pharmacologically the individualpharmacologically the individualenantiomers as well as any racemates.enantiomers as well as any racemates.


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'owever, it is often difficult to obtain'owever, it is often difficult to obtainspecific enantiomers in a pure state.specific enantiomers in a pure state.

-oth of these considerations make the-oth of these considerations make theproduction of optically active compoundsproduction of optically active compoundsepensive andepensive and so medicinal chemistsso medicinal chemistsoften prefer to synthesis leadoften prefer to synthesis lead

compounds that are not optically activecompounds that are not optically active..'owever, this is not always possible.'owever, this is not always possible.

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04/12/1604/12/16 prof. azaprof. aza 2020

)nce the structure of the proposed lead has)nce the structure of the proposed lead hasbeen decided it becomes the responsibility ofbeen decided it becomes the responsibility ofthe medicinal chemistthe medicinal chemist to devise a syntheticto devise a syntheticroute and prepare a sample of this compoundroute and prepare a sample of this compound

for testing.for testing. )nce synthesised, the compound undergoes)nce synthesised, the compound undergoesinitial pharmacological and toicologicalinitial pharmacological and toicologicaltesting. !he results of these tests enable thetesting. !he results of these tests enable theteam to decideteam to decide whether it is profitable towhether it is profitable to

continue developmentcontinue developmentby preparing analoguesby preparing analogues#$igure 2.1% because it is unlikely that the lead#$igure 2.1% because it is unlikely that the leadcompound It self will he suitable for use as acompound It self will he suitable for use as adrug.drug.


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!he usual scenario is!he usual scenario is to prepare a series ofto prepare a series ofanaloguesanaloguesand analyse the results of theirand analyse the results of theirbiological testing to determine the structurebiological testing to determine the structure

with optimum activity.with optimum activity. !his analysis may make use of A/!his analysis may make use of A/ ,,0A/0A/ ,,

computational chemistrycomputational chemistry,,and combinatorialand combinatorialchemistrychemistry,,to help discover the nature of thisto help discover the nature of thisstructure.structure.


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!he selection of a lead compound and!he selection of a lead compound andthe development of a synthetic pathwaythe development of a synthetic pathway

for its preparationfor its preparation is not the onlyis not the onlyconsideration at the start of anconsideration at the start of aninvestigation.investigation.

It is no use preparing a series ofIt is no use preparing a series of

compoundscompounds if there is no suitableif there is no suitabletesting procedure.testing procedure.


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/esearchers must also devise suitable in/esearchers must also devise suitable invivo and in vitro tests to assess thevivo and in vitro tests to assess theactivity and toicity of the compoundsactivity and toicity of the compoundsproduced.produced.

!here is no point in carrying out an!here is no point in carrying out anepensive synthetic procedureepensive synthetic procedure if at theif at the

end of the day it is impossible to testend of the day it is impossible to testthe product.the product.

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04/12/1604/12/16 prof. azaprof. aza 2424

!he processes of drug discovery!he processes of drug discoveryoutlined in this section areoutlined in this section are timetimeconsuming and epensive.consuming and epensive.

It takes about 1 years for a drug toIt takes about 1 years for a drug toreach the general public andreach the general public and only one inonly one inabout 1about 1 of the compounds preparedof the compounds prepared

is ever used.is ever used.


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04/12/1604/12/16 prof. azaprof. aza 2525

2.2 tereochemistry and Drug Design2.2 tereochemistry and Drug Design

IIttis now well established thatis now well established that thetheshape of a moleculeshape of a moleculeis normally one ofis normally one ofthe most important factors that affectthe most important factors that affectdrug activity. onsequently, the overalldrug activity. onsequently, the overall

shape of the structure of a molecule isshape of the structure of a molecule isan important consideration whenan important consideration whendesigning an analogue.designing an analogue.

ome structural features impose aome structural features impose a

considerable degree of rigidityconsiderable degree of rigidity into ainto astructure whereas others make thestructure whereas others make thestructurestructure more fleiblemore fleible..


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)ther structures give rise to)ther structures give rise tostereoisomers thatstereoisomers that can ehibitcan ehibitdifferent potencies, types ofdifferent potencies, types of

activity and unwanted side effectsactivity and unwanted side effects..

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It is necessary to consider all theseIt is necessary to consider all thesestereochemical features in the designstereochemical features in the designof a potential analogue.of a potential analogue.

'owever, the etent to which one can'owever, the etent to which one caneploit these structural features willeploit these structural features willdepend on our knowledge ofdepend on our knowledge of thethe

structure and biochemistry of thestructure and biochemistry of thetarget biological system.target biological system.

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04/12/1604/12/16 prof. azaprof. aza 2828

2.2.1 tructurally /igid roups2.2.1 tructurally /igid roups

roups that are structurally rigid areroups that are structurally rigid areunsaturated groups of all types andunsaturated groups of all types andsaturated ring systems #$iguresaturated ring systems #$igure 2.2%. !he2.2%. !heformer include esters and amides asformer include esters and amides aswell as aliphatic con(ugated systems andwell as aliphatic con(ugated systems andaromatic and heteroaromatic ringaromatic and heteroaromatic ringsystems.systems.

!he binding of these rigid structures to!he binding of these rigid structures toa target sitea target site can give information aboutcan give information aboutthe shape of that sitethe shape of that site as well as theas well as thenature of the interaction between thenature of the interaction between thesite and the ligand.site and the ligand.


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+(iphatic

co%j"#atiscs,stems

+romatic

s,tems

-eteroaromatic

s,stems


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/igid structures/igid structures

/igid structures may also be used/igid structures may also be used totodetermine the conformationdetermine the conformationassumed by aassumed by aligand when it binds to its target site.ligand when it binds to its target site.

$urthermore, the fact that the structure is$urthermore, the fact that the structure isrigid means that itrigid means that it may be replaced bymay be replaced byalternative rigid structures of a similar si3ealternative rigid structures of a similar si3eand shapeand shape to form analogues that may haveto form analogues that may have

different binding characteristics anddifferent binding characteristics andpossibly, as a result,possibly, as a result, a different activity ora different activity orpotencypotency

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04/12/1604/12/16 prof. azaprof. aza 3131

)i#"re 2.2. amp(es of str"ct"ra( #ro"ps that impose

a ri#i$ shape o% sectio%s of a mo(ec"(e. The sha$e$

areas represe%t the ri#i$ sectio%s of the mo(ec"(e.


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2.2.2. onformation2.2.2. onformation

4arly work in the 156s and early 157s4arly work in the 156s and early 157sby chueler and Archer suggested thatby chueler and Archer suggested thatthethe fleibility of the structures of bothfleibility of the structures of bothligands and receptorsligands and receptorsaccounted for theaccounted for thesame ligand being able to bind tosame ligand being able to bind todifferent subtypes of a receptor.different subtypes of a receptor.

Archer also concluded that a ligandArcher also concluded that a ligand

appeared to assumeappeared to assume differentdifferentconformationsconformations when it bound to thewhen it bound to thedifferent subtypes of a receptor.different subtypes of a receptor.


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$or eample, acetylcholine ehibits$or eample, acetylcholine ehibitsbothboth muscarinic and nicotinicmuscarinic and nicotinicactivity.activity.

Archer and collegues suggestedArcher and collegues suggestedthat thethat the muscarinic activity wasmuscarinic activity wasdue to the anti or staggereddue to the anti or staggered

conformationconformation whereas thewhereas the nicotinicnicotinicactivity was due to the syn oractivity was due to the syn oreclipsed formeclipsed form #$igure 2.8%.#$igure 2.8%.

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04/12/1604/12/16 prof. azaprof. aza 3434

)i#"re 2.3. ,% a%$ a%ti co%formers of

acet,(cho(i%e a%$ 2tropa%,( etha%oate

methio$i$es.


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04/12/1604/12/16 prof. azaprof. aza 3535

!hese workers based this suggestion on!hese workers based this suggestion ontheir observation that the antitheir observation that the anti

conformation of 2"tropanyl ethanoateconformation of 2"tropanyl ethanoatemethiodidesmethiodides preferentially binds topreferentially binds tomuscarinic receptorsmuscarinic receptors whereaswhereas the synthe synconformation binds preferentially toconformation binds preferentially to

nicotinic receptors.nicotinic receptors.


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!he structures of both of these compounds!he structures of both of these compoundscontain an acetylcholine residue locked in thecontain an acetylcholine residue locked in theappropriate conformation by the ringappropriate conformation by the ring

structure.structure. !his and subsequent investigations led to the!his and subsequent investigations led to the

conclusion that the development of analoguesconclusion that the development of analogueswith restricted or rigid conformationswith restricted or rigid conformations couldcould

result in the selective binding of drugs toresult in the selective binding of drugs totarget sites thattarget sites that could result in very activecould result in very activedrugs with reduced unwanted side effects.drugs with reduced unwanted side effects.

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04/12/1604/12/16 prof. azaprof. aza 3737

steric hindrance will prevent the bindingsteric hindrance will prevent the binding

!he main methods of introducing!he main methods of introducingconformational restrictions are by using bulkyconformational restrictions are by using bulkysubstituents, unsaturated structures or smallsubstituents, unsaturated structures or small

ring systems. mall ring systems are usuallyring systems. mall ring systems are usuallythe most popular choice #$igure 2.9%.the most popular choice #$igure 2.9%.

In all cases the structures used must beIn all cases the structures used must bechosen with care because there will always bechosen with care because there will always be

the possibility thatthe possibility that steric hindrance willsteric hindrance willprevent the bindingprevent the bindingof the analogue to theof the analogue to thetargettarget


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04/12/1604/12/16 prof. azaprof. aza 3838

$igure 2.9. 4amples of the use of conformationalrestrictions to produce analogues of #a% histamine and#b% do amine -onds marked with an asterisk canehibit tree rotation and form numerous conformers.


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'owever, if sufficient information is'owever, if sufficient information isavailable. omputer modeling can be ofavailable. omputer modeling can be ofconsiderable assistance in the choice ofconsiderable assistance in the choice of

structures.structures.A further limitation is knowing whichA further limitation is knowing which

bond to restrict.bond to restrict.

4ven in simple molecules numerous4ven in simple molecules numerouseclipsed, staggered and gaucheeclipsed, staggered and gaucheconformations are possible #$igure 2.6%.conformations are possible #$igure 2.6%.

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04/12/1604/12/16 prof. azaprof. aza 4040

)i#"re 2.5. amp(es of some of the major co%formatio%s

of the '1'2 bo%$ of acet,(cho(i%e. Other co%formatio%s

occ"r abo"t the ' a%$ 'O si%#(e bo%$s.


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04/12/1604/12/16 prof. azaprof. aza 4141

!he biological data obtained using!he biological data obtained usingrestricted conformation analogues canrestricted conformation analogues canbbe of use in determining the moste of use in determining the most

bioactive conformation of the ligand.bioactive conformation of the ligand.If the analogue ehibits either theIf the analogue ehibits either the

same or a greater degree of activity assame or a greater degree of activity as

the lead compound it ma: bethe lead compound it ma: be concludedconcludedthat the analogue has the correctthat the analogue has the correctconformation for binding to that siteconformation for binding to that site..


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'owever, if the analogue ehibits no'owever, if the analogue ehibits noactivity the result could he due toactivity the result could he due toeithereither ;;

steric hindrance between thesteric hindrance between therestricting group and the target orrestricting group and the target or

the analoguethe analogue having the incorrecthaving the incorrectconformation.conformation. In this case computerIn this case computermodeling may be of some assistance.modeling may be of some assistance.

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04/12/1604/12/16 prof. azaprof. aza 4343

2.2.8 onfiguration2.2.8 onfiguration

onfigurational centresonfigurational centres impose a rigidimpose a rigidshape on sections of the molecule inshape on sections of the molecule inwhich they occur.which they occur.

'owever, their presence gives rise to'owever, their presence gives rise togeometric and optical isomerism.geometric and optical isomerism.-ecause these-ecause these stereoisomers havestereoisomers have

different shapesdifferent shapes, biologically active, biologically activestereoisomers will often ehibitstereoisomers will often ehibitdifferences in their potencies and*ordifferences in their potencies and*oractivities #!able 2.1%.activities #!able 2.1%.


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04/12/1604/12/16 prof. azaprof. aza 4545

Tab(e 2.1. ariatio%s i% the bio(o#ica(actiities of stereoisomers.


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!hese pharmacological variations are!hese pharmacological variations areparticularly likely whenparticularly likely when a chiral centrea chiral centreis located in a critical position in theis located in a critical position in the

structure of the molecule.structure of the molecule.!he consequence of these differences!he consequence of these differences

is that it is now necessary to make andis that it is now necessary to make and

test separately all the individualtest separately all the individualstereoisomers of a drug.stereoisomers of a drug.

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04/12/1604/12/16 prof. azaprof. aza 4747

As well as an effect on the activity, differentAs well as an effect on the activity, differentstereoisorners will also change otherstereoisorners will also change otherphysiochemical properties suchphysiochemical properties such as absorption,as absorption,metabolism and elimination.metabolism and elimination.

$or eample, #"%"norgestrel is absorbed at$or eample, #"%"norgestrel is absorbed attwice the rate of #


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04/12/1604/12/16 prof. azaprof. aza 4949

2.8. tructure"Activity /elationships2.8. tructure"Activity /elationships#A/%#A/%

+ost drugs act at a specific site such as+ost drugs act at a specific site such asan en3yme or receptor. ompounds withan en3yme or receptor. ompounds withsimilar structures oftensimilar structures often tend to havetend to have

similar pharmacological activitysimilar pharmacological activity..'owever, they usually ehibit'owever, they usually ehibitdifferences in potency and unwanteddifferences in potency and unwanted

side effectsside effectsand in some casesand in some casesdifferent activities.different activities.


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!hese structurally related differences are!hese structurally related differences arecommonly referred to as structure activity"commonly referred to as structure activity"relationships #A/%.relationships #A/%.

A study of the structure"activityA study of the structure"activityrelationships of a lead compound and itsrelationships of a lead compound and itsanalogues can be usedanalogues can be used to determine the partsto determine the partsof the structure of the lead that areof the structure of the lead that are

responsible for its biological activity, that is,responsible for its biological activity, that is,its pharmacophoreits pharmacophoreand also its unwanted sideand also its unwanted sideeffects.effects.

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04/12/1604/12/16 prof. azaprof. aza 5151

!his information is subsequently used to!his information is subsequently used todevelop a new drug that has increaseddevelop a new drug that has increasedactivity #optimise its A/%.activity #optimise its A/%.

A different activity from an eistingA different activity from an eistingdrug, fewer unwanted side effects anddrug, fewer unwanted side effects andimproved ease of administration to theimproved ease of administration to the

patient.patient.


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04/12/1604/12/16 prof. azaprof. aza 5252

tructure"activity relationships aretructure"activity relationships areusually determinedusually determined by making minorby making minorchanges to the structure of the leadchanges to the structure of the lead

and assessing the effect that this hasand assessing the effect that this hason biological activity.on biological activity.!raditional A/ investigations are!raditional A/ investigations are

carried out by making large numbers ofcarried out by making large numbers of

analogues of the lead and testing themanalogues of the lead and testing themfor biological activity.for biological activity.


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)ver the years numerous lead)ver the years numerous leadcompounds have been investigated andcompounds have been investigated and

from the mass of data it is possible tofrom the mass of data it is possible tomake some broad generalisations aboutmake some broad generalisations aboutthe biological effects of specificthe biological effects of specific

structural changes.structural changes.

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These cha%#es ma, beThese cha%#es ma, be

co%e%ie%t(, c(assifie$ asco%e%ie%t(, c(assifie$ as

#1% the si3e and shape of the#1% the si3e and shape of thecarbon skeleton.carbon skeleton.#2% the nature and degree of#2% the nature and degree of

substitution, andsubstitution, and#8% the stereochemistry of the#8% the stereochemistry of the

lead.lead.

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04/12/1604/12/16 prof. azaprof. aza 5555

!he selection of the changes!he selection of the changesrequired to produce analogues of arequired to produce analogues of aparticular leadparticular lead is made byis made byconsidering the activities ofconsidering the activities ofcompounds with similar structurescompounds with similar structuresand also the possible chemistry andand also the possible chemistry and

biochemistry of the intendedbiochemistry of the intendedanalogue.analogue.


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$or eample$or eample

replacing a hydroy group with a methylreplacing a hydroy group with a methylgroupgroup could reduce the water solubilitycould reduce the water solubility of theof theanalogue and also its ability to hydrogen bond.analogue and also its ability to hydrogen bond.

!he former could!he former could reduce its ease ofreduce its ease ofabsorptionabsorptionwhereas the latter could affectwhereas the latter could affect itsitsabilitabilityyto bindto bind to its target site.to its target site.

It couldIt could improve the transport of the drugimprove the transport of the drug

through membranesthrough membranesand also introduceand also introducechanges in the metabolism of the drug.changes in the metabolism of the drug.

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$ l


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04/12/1604/12/16 prof. azaprof. aza 5757

$or eample$or eample,,

oidation of the methyl group to aoidation of the methyl group to acarboylic group couldcarboylic group could increase the rateincrease the rateof metabolism.of metabolism.All these effects couldAll these effects could

result in a loss of activity or a reductionresult in a loss of activity or a reductionin an unwanted side effect.in an unwanted side effect.A further considerationA further consideration is the si3e ofis the si3e of

the analogue.the analogue.hanging the structure ofhanging the structure of

the lead could result in an analogue thatthe lead could result in an analogue thatis too big to fit its intended target site.is too big to fit its intended target site.


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omputerised molecular modeling canomputerised molecular modeling can bbeeused to check this provided that theused to check this provided that thestructure of the target is known or canstructure of the target is known or can

he simulated with some degree ofhe simulated with some degree ofaccuracy.accuracy.!raditional A/ investigation!raditional A/ investigation

procedures are useful tools in theprocedures are useful tools in the

search for new drugs.search for new drugs.

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04/12/1604/12/16 prof. azaprof. aza 5959

'owever, they are epensive in both'owever, they are epensive in bothpersonnel and materials. onsequently, apersonnel and materials. onsequently, anumber of attempts have been made tonumber of attempts have been made toimprove on traditional structure"improve on traditional structure"activity investigations with varyingactivity investigations with varyingdegrees of success .degrees of success .


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04/12/1604/12/16 prof. azaprof. aza 6060

2.8.1 hanging i3e and hape2.8.1 hanging i3e and hape

!he shapes and si3es of molecules can be!he shapes and si3es of molecules can bemodified in a variety of ways, such as;modified in a variety of ways, such as;

#i% changing#i% changing the number of methylenethe number of methylenegroups in chains and ringsgroups in chains and rings;; #ii% increasing or decreasing#ii% increasing or decreasing the degreethe degree

of unsaturationof unsaturation;; #iii%#iii% introducing or removing a ringintroducing or removing a ring

system.system.

2 8 8 1 h i h > b f2 8 8 1 h i th > b f


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04/12/1604/12/16 prof. azaprof. aza 6161

2.8.8.1 hanging the >umber of2.8.8.1 hanging the >umber of+ethylene roups in a hain+ethylene roups in a hain

Increasing the number of methyleneIncreasing the number of methylenegroups in a chain or ringgroups in a chain or ring increases theincreases thesi3e and the lipid nature #lipophilicity%si3e and the lipid nature #lipophilicity%of the compound.of the compound.

!he biological response curves!he biological response curvesassociated with this increase in si3e canassociated with this increase in si3e can

assume a variety of shapes #$igureassume a variety of shapes #$igure2.7a%.2.7a%.


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It is believed that the increase in activityIt is believed that the increase in activitywith increase in the number of methylenewith increase in the number of methylenegroups is probably duegroups is probably due to an increase in theto an increase in the

lipid solubility of the analogue, which gives alipid solubility of the analogue, which gives abetter membrane penetration.better membrane penetration. onverselyonversely, a decrease in activity, a decrease in activity #$igure#$igure

2.7b% with an increase in the number of2.7b% with an increase in the number of

methylene groups is attributed to a reductionmethylene groups is attributed to a reductionin the water solubility of the analogues.in the water solubility of the analogues.

04/12/1604/12/16 prof. azaprof. aza 6262


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04/12/1604/12/16 prof. azaprof. aza 6363

)i#"re 2.6. amp(es of the ariatio% of respo%se c"res *ith i%creasi%# %"mbers of

i%serte$ meth1e%e #ro"ps. a + st"$, b, !ohme a%$ co((e#"es o% the ariatio% of

a%tibacteria( actiit, of 4a,(s"hstit"te$ resorci%o(s. h %hibitio% of a%#iote%si%

co%erti%# e%z,me b, e%a(apri(at a%a(o#"es Thorseti. The a("es i% pare%theses are

'50 a("es for those a%a(o#"es.


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04/12/1604/12/16 prof. azaprof. aza 6464

!his reduction in water solubility can!his reduction in water solubility canresultresult in the poor distribution of thein the poor distribution of theanalogue in tile aqueous mediaanalogue in tile aqueous mediaas well asas well as

the trapping of the analogue inthe trapping of the analogue inbiological membranesbiological membranes ..


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micelle formationmicelle formation

A further problem with large increasesA further problem with large increasesin the numbers of inserted methylenein the numbers of inserted methylenegroups in chain structures isgroups in chain structures is micellemicelle

formationformation..+icelle formation produces large+icelle formation produces large

aggregates that, because of theiraggregates that, because of their

shape,shape, cannot bind to active sitescannot bind to active sites andandreceptors.receptors.

04/12/1604/12/16 prof. azaprof. aza 6565


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04/12/1604/12/16 prof. azaprof. aza 6666

Introducing chain branching, differentIntroducing chain branching, differentsi3ed rings and the substitution ofsi3ed rings and the substitution ofchains for ringschains for ringsand vice versa may alsoand vice versa may also

have an effect on the potency and typehave an effect on the potency and typeof activity of analogues.of activity of analogues.

$or eample, the replacement of the$or eample, the replacement of the

sulphursulphuratom of the antipsychoticatom of the antipsychoticchlorproma3inechlorproma3ine by ?'2"'2"by ?'2"'2" producesproducesthe antidepressant clomiprarnine.the antidepressant clomiprarnine.

2 8 1 2 h i th D f2 8 1 2 h i th D f


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04/12/1604/12/16 prof. azaprof. aza 6767

2.8.1.2 hanging the Degree of2.8.1.2 hanging the Degree of@nsaturafion@nsaturafion

!he removal of double bonds!he removal of double bondsincreases the degree of fleibilityincreases the degree of fleibility

of the molecule, which may make itof the molecule, which may make iteasier for the analogue to fit intoeasier for the analogue to fit intoactive and receptoractive and receptorsites by takingsites by takingup a more suitable conformation.up a more suitable conformation.

'owever,'owever, an increase in fleibilityan increase in fleibilitycould also result in a change or losscould also result in a change or lossof activity.of activity.


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!he introduction of a double bond!he introduction of a double bond increasesincreasesthe rigiditythe rigidity of the structure. It may alsoof the structure. It may alsointroduce the complication of 4" and "introduce the complication of 4" and "

isomers, which could have quite differentisomers, which could have quite differentactivities #see !able 2.1%.activities #see !able 2.1%. !he analogues produced by the introduction!he analogues produced by the introduction

of unsaturated structures into a leadof unsaturated structures into a lead

compoundcompound may ehibit different degrees ofmay ehibit different degrees ofpotency or different types of activitiespotency or different types of activities

04/12/1604/12/16 prof. azaprof. aza 6868


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$or eample,$or eample, the potency of prednisonethe potency of prednisoneis about 8 times greater than that ofis about 8 times greater than that ofits parent compound cortisolits parent compound cortisol, which does, which does

not have a 1"2not have a 1"2 B bondB bond..!he replacement of the atom of the!he replacement of the atom of the

antipsychotic phenothia3ine drugs by a ?antipsychotic phenothia3ine drugs by a ?

'B'" group gives the antidepressant'B'" group gives the antidepressantdiben3a3epine drugs, such asdiben3a3epine drugs, such asprotriptyline.protriptyline.

04/12/1604/12/16 prof. azaprof. aza 6969


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04/12/1604/12/16 prof. azaprof. aza 7070


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!he introduction of a B group will!he introduction of a B group willoften give analogues that areoften give analogues that are moremoresensitive to metabolic oidation.sensitive to metabolic oidation.

!his may or may not be a desirable!his may or may not be a desirablefeature for the new drug. $urthermore,feature for the new drug. $urthermore,the reactivity of B frequently causesthe reactivity of B frequently causes

the analogue tothe analogue to bbe more toic than thee more toic than thelead.lead.

04/12/1604/12/16 prof. azaprof. aza 7171

2 8 1 8 Introduction or /emoval of a /ing2 8 1 8 Introduction or /emoval of a /ing


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04/12/1604/12/16 prof. azaprof. aza 7272

2.8.1.8 Introduction or /emoval of a /ing2.8.1.8 Introduction or /emoval of a /ingystemystem

!he introduction of a ring system!he introduction of a ring systemchanges the shapechanges the shape and increases theand increases theoverall si3eoverall si3e of the analogue.of the analogue.

!he effect of these changes on the!he effect of these changes on thepotency and activity of the analogue ispotency and activity of the analogue isnot generally predictablenot generally predictable. 'owever, the. 'owever, theincrease in si3e can be useful in filling aincrease in si3e can be useful in filling a

hydrophobic pocket in a target site,hydrophobic pocket in a target site,which mightwhich might strengthen the binding ofstrengthen the binding ofthe drug to the target.the drug to the target.


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$or eample$or eample

it has been postulated that theit has been postulated that theincreased inhibitory activity of theincreased inhibitory activity of thecyclopentyl analogue #rolipram% of 8"cyclopentyl analogue #rolipram% of 8"

#8,9"dimethyloyphenyl%"butyrolactam#8,9"dimethyloyphenyl%"butyrolactamtowards cA+C phosphodiesterase is duetowards cA+C phosphodiesterase is dueto theto the cyclopentyl group filling acyclopentyl group filling a

hydrophobic pockethydrophobic pocketin the active site ofin the active site ofthis en3yme.this en3yme.

04/12/1604/12/16 prof. azaprof. aza 7373


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04/12/1604/12/16 prof. azaprof. aza 7474


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!he incorporation of smaller, as against!he incorporation of smaller, as againstlarger, alicyclic ring systems into a leadlarger, alicyclic ring systems into a leadstructurestructure reduces the possibility of producingreduces the possibility of producing

an analogue that is too bigan analogue that is too bigfor its target site.for its target site. It also reduces the possibility of complicationIt also reduces the possibility of complication

caused by tile eistence of conformers.caused by tile eistence of conformers.'owever. the selection of the system for a'owever. the selection of the system for a

particular analogue may depend on theparticular analogue may depend on theob(ective of the alteration.ob(ective of the alteration.

04/12/1604/12/16 prof. azaprof. aza 7575

l


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$or eample,$or eample,

the cyclopropane ring is usually morethe cyclopropane ring is usually morestable than the ethylenic B groupstable than the ethylenic B groupand so could be used to replace thisand so could be used to replace this

group if a more stable compound of agroup if a more stable compound of asimilar si3e is required.similar si3e is required.

$or eample, the antidepressant$or eample, the antidepressanttranylcypromine is more stable thantranylcypromine is more stable than

its analogue 1 "amino"2"its analogue 1 "amino"2"phpheenylethene.nylethene.

04/12/1604/12/16 prof. azaprof. aza 7676


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04/12/1604/12/16 prof. azaprof. aza 7777

aromatic systemsaromatic systems


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04/12/1604/12/16 prof. azaprof. aza 7878

aromatic systemsaromatic systems!he insertion of aromatic systems!he insertion of aromatic systems

into the structure of the lead willinto the structure of the lead willintroduce rigidityintroduce rigidity into theinto thestructure as well asstructure as well as increase theincrease the

si3e of the analogue.si3e of the analogue.!he latter means that small!he latter means that small

aromatic systems such asaromatic systems such as ben3eneben3ene

and five"membered heterocyclicand five"membered heterocyclicsytemssytemsare often preferred toare often preferred tolarger systems.larger systems.


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'owever, the'owever, the electrons of aromaticelectrons of aromaticsystemssystems may or may not improve themay or may not improve thebinding of the analogue to its targetbinding of the analogue to its target

site.site.$urthermore, heterocyclic aromatic$urthermore, heterocyclic aromatic

systems will alsosystems will also introduce etraintroduce etra

functional groups into the structurefunctional groups into the structure,,which could also affect the potency andwhich could also affect the potency andactivity of the analogue.activity of the analogue.

04/12/1604/12/16 prof. azaprof. aza 7979

l$ l


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the resistance of diphenicillin tothe resistance of diphenicillin to EE"lactamase"lactamaseis believed to be due to theis believed to be due to the diphenyl groupdiphenyl grouppreventing the en3yme from reaching thepreventing the en3yme from reaching the EE

""lactam.lactam. It is interesting to note that 2"It is interesting to note that 2"

phenylhen3ylpenicillin is not resistant tophenylhen3ylpenicillin is not resistant to EE"lactamase attack. In this case, it appears"lactamase attack. In this case, it appears

that thethat the diphenyl group is too far away fromdiphenyl group is too far away fromthethe EE"lactam ring"lactam ring to hinder the attack of theto hinder the attack of theEE"lactamase."lactamase.

04/12/1604/12/16 prof. azaprof. aza 8080


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04/12/1604/12/16 prof. azaprof. aza 8181

$ l$ l


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the replacement of thethe replacement of the >"dimethyl>"dimethylgroupgroupof chlorproma3ine by anof chlorproma3ine by an >">"mmethylpipera3ine groupethylpipera3ine groupproduces anproduces an

analogue #prochlorpera3ine% withanalogue #prochlorpera3ine% withincreased antiemetic potencyincreased antiemetic potency bbututreduced neuroleptic activity.reduced neuroleptic activity.

It has been suggested that thisIt has been suggested that this

change in activity could be due tochange in activity could be due to thethepresence of the etra tertiary"aminepresence of the etra tertiary"amine

group.group.04/12/1604/12/16 prof. azaprof. aza 8282


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04/12/1604/12/16 prof. azaprof. aza 8383


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04/12/1604/12/16 prof. azaprof. aza 8484

!he incorporation of ring systems,!he incorporation of ring systems,especially larger systems, into theespecially larger systems, into thestructure of a lead can be used tostructure of a lead can be used to

produce analogues that areproduce analogues that areresistant to en3yresistant to en3ymmic attackic attack bybysterically hindering the access ofsterically hindering the access ofthe en3yme to the relevantthe en3yme to the relevant

functional group.functional group.

) () (


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)or eamp(e:)or eamp(e:

the resistance of diphenicillin tothe resistance of diphenicillin to EE"lactamase"lactamaseis believed to be due to theis believed to be due to the diphenyl groupdiphenyl grouppreventing the en3yme from reaching thepreventing the en3yme from reaching the EE

"lactam"lactam.. It is interesting to note that 2"It is interesting to note that 2"

phenylphenylbben3ylpenicillin is not resistant toen3ylpenicillin is not resistant to EE"lactamase attack. In this case, it appears"lactamase attack. In this case, it appears

thatthat the diphenyl group is too far away fromthe diphenyl group is too far away fromthethe EE"lactam ring"lactam ringto hinder the attack of theto hinder the attack of theEE"lactamase."lactamase.

04/12/1604/12/16 prof. azaprof. aza 8585


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04/12/1604/12/16 prof. azaprof. aza 8686

+any of the potent+any of the potentpharmacologically active naturallypharmacologically active naturallyoccurring compounds, such as theoccurring compounds, such as the

alkaloids morphine and curare, havealkaloids morphine and curare, havesuch comple structures that itsuch comple structures that itwould notwould not bbe economic toe economic tosynthesise them on a large scale.synthesise them on a large scale.$urthermore, they also tend to$urthermore, they also tend toehibit unwanted side effects.ehibit unwanted side effects.


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'owever, the structures of many of these'owever, the structures of many of thesecompounds contain several ring systems.compounds contain several ring systems.

In these cases, one approach to designingIn these cases, one approach to designing

analogues of these compounds centres aroundanalogues of these compounds centres arounddetermining the pharmacophore and removingdetermining the pharmacophore and removingany surplus ring structuresany surplus ring structures. It is hoped that. It is hoped thatthis will also result in the loss of any unwantedthis will also result in the loss of any unwanted

side effects. !he classic eample illustratingside effects. !he classic eample illustratingthis type of approach is the development ofthis type of approach is the development ofdrugs from morphine #$igure 2.F%.drugs from morphine #$igure 2.F%.

04/12/1604/12/16 prof. azaprof. aza 8787


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It is hoped that this will also result inIt is hoped that this will also result inthe loss of any unwanted side effectsthe loss of any unwanted side effects..!he classic eample illustrating this!he classic eample illustrating this

type of approach is the development oftype of approach is the development ofdrugs from morphine #$igure 2.F%.drugs from morphine #$igure 2.F%.

04/12/1604/12/16 prof. azaprof. aza 8888


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04/12/1604/12/16 prof. azaprof. aza 8989


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04/12/1604/12/16 prof. azaprof. aza 9090

$igure 2.F. !he pharmacophore of morphine

was found to be the structure represented bythe bonds in heavy type. Cruning andmodification of the remaining structure ofmorphine resulted in the developmcnt of #a%the more potent but still highly addictivelevorphanol, #b% the very much less potentpethidine, #c% the less potent and less

addictive penta3ocine and #d% the equallypotent but much less addictive methadone,amongst other drugs.

2 8 2 Intr ducti n f >2 8 2 Introduction of >ew


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04/12/1604/12/16 prof. azaprof. aza 9191

2.8.2 Introduction of >ew2.8.2 Introduction of >ewubstituentsubstituents

!he formation of analogues by!he formation of analogues bythe introduction of newthe introduction of newsubstituents into the structuresubstituents into the structureof a lead mayof a lead may result in anresult in ananalogue with significantlyanalogue with significantly

different chemical and hencedifferent chemical and hencepharmacokinetic propertiespharmacokinetic properties..


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$or eample, the introduction of a new$or eample, the introduction of a new

substituent maysubstituent may cause significantcause significantchanges in lipophilicity that affectchanges in lipophilicity that affecttransport of the analoguetransport of the analogue throughthrough

membranes and the various fluids foundmembranes and the various fluids foundin the body.in the body.

It would also change the shapeIt would also change the shape,,whichwhich

could result in conformationalcould result in conformationalrestrictions that affect the binding torestrictions that affect the binding tothe target site.the target site.

04/12/1604/12/16 prof. azaprof. aza 9292

the presence of a new groupthe presence of a new group


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04/12/1604/12/16 prof. azaprof. aza 9393

the presence of a new groupthe presence of a new group

In addition, the presence of a new groupIn addition, the presence of a new groupmaymay introduce a new metabolic pathwayintroduce a new metabolic pathwayfor the analogue.for the analogue.

!hese changes will in turn affect the!hese changes will in turn affect the

pharmacodynamic properties of thepharmacodynamic properties of theanalogue.analogue.$or eample, they could result in an$or eample, they could result in an

analogue withanalogue with either increased oreither increased or

decreased potency, duration of action,decreased potency, duration of action,metabolic stability and unwanted sidemetabolic stability and unwanted sideeffects.effects.


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!he choice of substituent will depend on!he choice of substituent will depend onthe properties that the developmentthe properties that the developmentteam decide to enhance in an attempt toteam decide to enhance in an attempt tomeet their ob(ectives. 4ach substituentmeet their ob(ectives. 4ach substituentwill impart its own characteristicwill impart its own characteristicproperties to the analogue.properties to the analogue.

'owever, it is possible to generalise'owever, it is possible to generaliseabout the effect of introducing a newabout the effect of introducing a newsubstituent group into a structure butsubstituent group into a structure butthere willthere will bbe numerous eceptions to thee numerous eceptions to thepredictions.predictions.

04/12/1604/12/16 prof. azaprof. aza 9494

2 8 2 1 + th l s2 8 2 1 +ethyl roups


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04/12/1604/12/16 prof. azaprof. aza 9595

2.8.2.1 +ethyl roups2.8.2.1 +ethyl roups

!he introduction of methyl groups!he introduction of methyl groupsusuallyusually increases the lipophilicityincreases the lipophilicity of theof thecompound andcompound and reduces its waterreduces its water

solubilitysolubility#!able 2.2%.#!able 2.2%.It should improveIt should improve the ease of absorptionthe ease of absorption

of the analogue into a biologicalof the analogue into a biological

membranemembrane ,bu,but will maket will make its releaseits release fromfrombiological membranes into the aqueousbiological membranes into the aqueousmediamedia more difficultmore difficult..


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04/12/1604/12/16 prof. azaprof. aza 9696

!able 2.2. !he change in the partition

coefficients #C% of some commoncompounds when methyl groups areintroduced into their structures.

!he greater the value of C the more lipid"soluble the compound. -en3ene andtoluene values were measured using an n"octanol*water system and the remainingvalues were measured using an oliveoil*water system.


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04/12/1604/12/16 prof. azaprof. aza 9797


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04/12/1604/12/16 prof. azaprof. aza 9898

!he incorporation of a methyl group!he incorporation of a methyl groupcan imposecan impose steric restrictionssteric restrictions ononthe structure of an analogue.the structure of an analogue.

$or eample, the ortho"methyl$or eample, the ortho"methylanalogue of diphenhydramineanalogue of diphenhydramineehibits no antihistamine activity.ehibits no antihistamine activity.

Ortho/para s"btit"e%tOrtho/para s"btit"e%t


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Ortho/para s"btit"e%tOrtho/para s"btit"e%t

'armes and collegues suggest that this'armes and collegues suggest that thiscould be due to thecould be due to the ortho"methyl grouportho"methyl grouprestricting rotation about the ") bondrestricting rotation about the ") bondof the side chainof the side chain. !his prevents the. !his prevents the

molecule from adopting themolecule from adopting theconformation necessary forconformation necessary forantihistamine activity.antihistamine activity.

It is interesting to note that the para"It is interesting to note that the para"methyl analogue is 8.F times more activemethyl analogue is 8.F times more activethan diphenhydramine.than diphenhydramine.

04/12/1604/12/16 prof. azaprof. aza 9999


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04/12/1604/12/16 prof. azaprof. aza 100100

The i%corporatio% of a meth,(The i%corporatio% of a meth,(


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04/12/1604/12/16 prof. azaprof. aza 101101

The i%corporatio% of a meth,(The i%corporatio% of a meth,(

#ro"p#ro"pcan have one of three general effects on thecan have one of three general effects on the

rate of metabolism of an analogue;rate of metabolism of an analogue; #i%#i% an increased rate of metabolisman increased rate of metabolism due todue to

oidation of the methyl groupGoidation of the methyl groupG #ii%#ii% an increase in the rate of metabolisman increase in the rate of metabolism duedue

to demethylation by the transfer of theto demethylation by the transfer of themethyl group to another compoundG or amethyl group to another compoundG or a

reduction in the rate of metabolism of thereduction in the rate of metabolism of theanalogue.analogue.


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04/12/1604/12/16 prof. azaprof. aza 102102

#i% A methyl group bound to an aromatic ringor a structure which increases its

reactivity may be metabolised to acarboylic acid, which can be eliminatedmore easily.

#ii%$or eample, the antidiabetic tolbutamideis metabolised to its less toic ben3oicacid derivative. !he introduction of areactive "' group offers a

detoification route for lead compoundsthat are too toic to be of use.


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04/12/1604/12/16 prof. azaprof. aza 103103

associated with carcinogenic actionassociated with carcinogenic action


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04/12/1604/12/16 prof. azaprof. aza 104104

associated with carcinogenic actionassociated with carcinogenic action

ii% Demethylation is more likely to occurii% Demethylation is more likely to occurwhen the methyl group is attachedwhen the methyl group is attached totopositively charged nitrogen and sulphurpositively charged nitrogen and sulphuratomsatoms, although it is possible for any, although it is possible for any

methyl group attached to a nitrogen,methyl group attached to a nitrogen,oygen or sulphur atom to act in thisoygen or sulphur atom to act in thismanner.manner.

A number ofA number of methyl transfers have beenmethyl transfers have beenassociated with carcinogenic actionassociated with carcinogenic action..


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04/12/1604/12/16 prof. azaprof. aza 105105

#iii% +ethyl groups can#iii% +ethyl groups can reduce the ratereduce the rate

of metabolism of a compound by maskingof metabolism of a compound by maskinga metabolically active groupa metabolically active group, thereby, therebygiving the analogue a slower rate ofgiving the analogue a slower rate ofmetabolism than the lead.metabolism than the lead.

$or eample, the action of the$or eample, the action of theagricultural fungicide nabam is due to itagricultural fungicide nabam is due to itbeing metabolised to the activebeing metabolised to the activediisothiocyanate.diisothiocyanate. >"+ethylation of>"+ethylation ofnabam yields an analogue that is inactivenabam yields an analogue that is inactivebecause it cannot be metabolised to thebecause it cannot be metabolised to theactive diisothiocyanate.active diisothiocyanate.


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04/12/1604/12/16 prof. azaprof. aza 106106

+ethylation can also reduce the


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04/12/1604/12/16 prof. azaprof. aza 107107

+ethylation can also reduce theunwanted side effects of a drug.

$or eample, mono" and diortho"methylation with respect to thephenolic hydroy group of paracetamol

produce analogues with reducedhepatotoicity.It is believed that this reduction is dueto the methyl groups preventingmetabolic hydroylation of these orthopositions.


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04/12/1604/12/16 prof. azaprof. aza 108108

methyl and ethyl groupsmethyl and ethyl groups


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04/12/1604/12/16 prof. azaprof. aza 109109

methyl and ethyl groupsmethyl and ethyl groups

&arger alkyl groups will have similar&arger alkyl groups will have similareffects. 'owever, as the si3e of theeffects. 'owever, as the si3e of the

group increases, the lipophilicity willgroup increases, the lipophilicity willreach a point where it reduces thereach a point where it reduces thewater solubility to an impractical level.water solubility to an impractical level.

onsequently,onsequently, most substitutions aremost substitutions arerestricted to methyl and ethyl groupsrestricted to methyl and ethyl groups..

2 8 2 2 'alogen roups2 8 2 2 'alogen roups


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04/12/1604/12/16 prof. azaprof. aza 110110

2.8.2.2 'alogen roups2.8.2.2 'alogen roups

!he incorporation of halogen atoms into!he incorporation of halogen atoms intoa lead results in analogues that area lead results in analogues that aremore lipophilic and so less water soluble.more lipophilic and so less water soluble.

onsequently,onsequently, halogen atoms are used tohalogen atoms are used toimprove the penetration of lipidimprove the penetration of lipidmembranes.membranes.

'owever, there is an undesirable'owever, there is an undesirable

tendency for halogenated drugs totendency for halogenated drugs toaccumulate in lipid tissue.accumulate in lipid tissue.


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04/12/1604/12/16 prof. azaprof. aza 111111

!he chemical reactivity of halogen!he chemical reactivity of halogenatoms depends on both their point ofatoms depends on both their point ofattachment to the lead and the natureattachment to the lead and the nature

of the halogen.of the halogen.Aromatic halogen groups are far lessAromatic halogen groups are far less

reactive than aliphatic halogen groupsreactive than aliphatic halogen groups,,which can ehibit considerable chemicalwhich can ehibit considerable chemicalreactivity.reactivity.


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$or aliphatic carbon"halogen bonds the$or aliphatic carbon"halogen bonds the"$ bond is the strongest and usually"$ bond is the strongest and usuallylessless #moreH%#moreH% chemically reactive thanchemically reactive than

aliphatic "' bondsaliphatic "' bonds..!he other aliphatic "halogen bonds are!he other aliphatic "halogen bonds are

weaker, their reactivity increasing downweaker, their reactivity increasing down

the periodic table. !hey are usually morethe periodic table. !hey are usually morechemically reactive than aliphatic "'chemically reactive than aliphatic "'bonds.bonds.

04/12/1604/12/16 prof. azaprof. aza 112112


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04/12/1604/12/16 prof. azaprof. aza 113113

onsequently, the most popularonsequently, the most popularhalogen substitutions are the lesshalogen substitutions are the lessreactive aromatic fluorine andreactive aromatic fluorine and

chlorine groups.chlorine groups.'owever, the presence of electron"'owever, the presence of electron"

withdrawing ring substituents maywithdrawing ring substituents may

increase their reactivity toincrease their reactivity tounacceptable levels.unacceptable levels.


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!rifluorocarbon groups #"$!rifluorocarbon groups #"$88% are some"times% are some"timesused to replace chlorine because these groupsused to replace chlorine because these groupsare of a similar si3e.are of a similar si3e.

!hese substitutions!hese substitutions avoid introducing a veryavoid introducing a veryreactive centrereactive centre and hence a possible site forand hence a possible site forunwanted side reactions into the analogue.unwanted side reactions into the analogue.

$or eample, the introduction of the more$or eample, the introduction of the more

reactive bromo group can cause the drug toreactive bromo group can cause the drug toactact as an alkylaling agentas an alkylaling agent..

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04/12/1604/12/16 prof. azaprof. aza 115115

The cha%#es i% pote%c, ca"se$ b, theThe cha%#es i% pote%c, ca"se$ b, thei%tro$"ctio% of a ha(o#e% or ha(o#e%co%tai%i%#i%tro$"ctio% of a ha(o#e% or ha(o#e%co%tai%i%##ro"p *i((: as *ith s"bstit"tio% b, other#ro"p *i((: as *ith s"bstit"tio% b, others"bstit"e%ts: $epe%$ o% the positio% of thes"bstit"e%ts: $epe%$ o% the positio% of the

s"bstit"tio%.s"bstit"tio%. )or eamp(e: the a%tih,perte%sie c(o%i$i%e *ith)or eamp(e: the a%tih,perte%sie c(o%i$i%e *ith

its o:o;ch(oro s"bstit"tio% is more pote%t tha% itsits o:o;ch(oro s"bstit"tio% is more pote%t tha% itsp:m$ich(oro a%a(o#"e. t is be(iee$ that thep:m$ich(oro a%a(o#"e. t is be(iee$ that the

b"(, och(ori%e #ro"ps impose a co%formatio%a(b"(, och(ori%e #ro"ps impose a co%formatio%a(restrictio% o% the str"ct"re of c(o%i$i%e: *hichrestrictio% o% the str"ct"re of c(o%i$i%e: *hichprobab(, acco"%ts for its i%crease$ actiit,.probab(, acco"%ts for its i%crease$ actiit,.


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$or eample, the antihypertensive$or eample, the antihypertensiveclonidine with its o,o:"chloroclonidine with its o,o:"chlorosubstitution is more potent than its p,m"substitution is more potent than its p,m"

dichloro analogue.dichloro analogue.

It is believed that the bulkyIt is believed that the bulky o"chlorineo"chlorinegroups impose a conformationalgroups impose a conformationalrestriction on the structure ofrestriction on the structure ofclonidine,clonidine, which probably accounts forwhich probably accounts forits increased activity.its increased activity.

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2 8 2 8 'ydroy roups2.8.2.8 'ydroy roups


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04/12/1604/12/16 prof. azaprof. aza 118118

2.8.2.8 'ydroy roups2.8.2.8 'ydroy roups

!he introduction of hydroy groups in!he introduction of hydroy groups intoto thethestructure of a lead will normallystructure of a lead will normallyproduce analogues withproduce analogues with an increasedan increasedhydrophilic nature and a lower lipidhydrophilic nature and a lower lipid

solubility.solubility.It alsoIt also provides a new centre forprovides a new centre for

hydrogen bondinghydrogen bonding, which could influence, which could influence

the binding of the analogue to its targetthe binding of the analogue to its targetsite.site.


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$or eample, the ortho"hydroylated$or eample, the ortho"hydroylated

minaprine analogue binds moreminaprine analogue binds moreeffectively to +effectively to +11"muscarinic receptors"muscarinic receptorsthan many of its non"hydroylatedthan many of its non"hydroylated

analogues.analogues.

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!he introduction of a hydroy group also!he introduction of a hydroy group alsointroduces a centre that,introduces a centre that, in the case ofin the case ofphenolic groups, could act as aphenolic groups, could act as abacterioside whereas alcohols havebacterioside whereas alcohols have

narcotic properties.narcotic properties.'owever, the presence of hydroy'owever, the presence of hydroy

groups opens a new metabolic pathwaygroups opens a new metabolic pathway

that can either actthat can either act as a detoificationas a detoificationrouteroute oror prevent the drug from reachingprevent the drug from reachingits target.its target.

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2.8.2.9 -asic roups2.8.2.9 -asic roups


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04/12/1604/12/16 prof. azaprof. aza 121121

2.8.2.9 -asic roups2.8.2.9 -asic roups

!he basic groups usually found in drugs!he basic groups usually found in drugsare amines, including some ring nitrogenare amines, including some ring nitrogenatomsatoms amidines and guanidines.amidines and guanidines.

All these basic groups can form salts inAll these basic groups can form salts inbiological media. onsequently,biological media. onsequently,incorporation of these basic groups intoincorporation of these basic groups intothe structure of a lead will producethe structure of a lead will produce

analoguesanalogues that have a lower lipophilicitythat have a lower lipophilicitybut an increased water solubilitybut an increased water solubility ..


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!his means that!his means that the more basic anthe more basic ananalogue, the more likely it will formanalogue, the more likely it will formsalts and the less likely it will besalts and the less likely it will be

transported through a lipid membrane.transported through a lipid membrane.

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04/12/1604/12/16 prof. azaprof. aza 123123

!he introduction of basic groups may!he introduction of basic groups mayincrease the binding of an analogueincrease the binding of an analogue totoits target by hydrogen bonding betweenits target by hydrogen bonding betweenthat target and the basic group #$igurethat target and the basic group #$igure

2.a%.2.a%.'owever, a number of drugs with basic'owever, a number of drugs with basic

groups owe their activity to saltgroups owe their activity to saltformation and the enhanced binding thatformation and the enhanced binding thatoccurs dueoccurs due to the ionic bonding betweento the ionic bonding betweenthe drug and the targetthe drug and the target #$igure 2.%.#$igure 2.%.


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)or eamp(e. it is be(iee$ that ma%, (oca()or eamp(e. it is be(iee$ that ma%, (oca(a%aesthetics are tra%sporte$ to their sitea%aesthetics are tra%sporte$ to their siteof actio% i% the form of their free bases b"tof actio% i% the form of their free bases b"tare co%erte$ to their sa(ts *hich hi%$ toare co%erte$ to their sa(ts *hich hi%$ to

the appropriate receptor sites.the appropriate receptor sites.The i%corporatio% of aromatic ami%es i%toThe i%corporatio% of aromatic ami%es i%to

the str"ct"re of a (ea$ is "s"a((, aoi$e$the str"ct"re of a (ea$ is "s"a((, aoi$e$beca"se aromatic ami%es are ofte% er,beca"se aromatic ami%es are ofte% er,toic a%$ are ofte% carci%o#e%ic.toic a%$ are ofte% carci%o#e%ic.

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04/12/1604/12/16 prof. azaprof. aza 125125

$igure 2.. Cossible sites of #a% hydrogenbonding between a target site and aminogroups and #b% ionic bonding between aminesalts and a target site.

2.3.2.5 'arbo,(ic a%$ "(pho%ic +ci$2.3.2.5 'arbo,(ic a%$ "(pho%ic +ci$

Gro"psGro"ps


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04/12/1604/12/16 prof. azaprof. aza 126126

Gro"psGro"ps

!he introduction of carboylic acid!he introduction of carboylic acidgroups into small lead molecules maygroups into small lead molecules mayproduce analogues that haveproduce analogues that have a verya verydifferent type of activity or are inactive.different type of activity or are inactive.

$or eample, the introduction of a$or eample, the introduction of acarboylic acid group into phenol resultscarboylic acid group into phenol resultsin the activity of the compound changingin the activity of the compound changing

from beingfrom being a toic antiseptic to the lessa toic antiseptic to the lesstoic anti"inflammatory salicylic acid.toic anti"inflammatory salicylic acid.


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imilarly, the incorporation of aimilarly, the incorporation of acarboylic acid group into thecarboylic acid group into thesympathomimetic phenylethylaminesympathomimetic phenylethylamine

gives phenylalanine, which has nogives phenylalanine, which has nosympathomimetic activity.sympathomimetic activity.

'owever, the introduction of carboylic'owever, the introduction of carboylic

acid groups appears to have less effectacid groups appears to have less effecton the activity of large molecules.on the activity of large molecules.

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ulphonic acid groups do not usually have any

effect on the biological activity but willincrease the rate of elimination of ananalogue.

2.3.2.6 Thio(s: "(phi$es a%$ Other2.3.2.6 Thio(s: "(phi$es a%$ Other

( h G"(ph"r Gro"ps


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"(ph"r Gro"ps"(ph"r Gro"ps

!hiol and sulphide groups are!hiol and sulphide groups are notnotusually introduced into leads in A/usually introduced into leads in A/studies because they are readilystudies because they are readilymetabolised by oidation.metabolised by oidation.

'owever, thiols are some times'owever, thiols are some timesintroduced into a lead structureintroduced into a lead structure

whenwhen improved metal chelationimproved metal chelation isisthe ob(ective of the A/ study.the ob(ective of the A/ study.


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$or eample, the antihypertensive$or eample, the antihypertensivecaptopril was developed from the weaklycaptopril was developed from the weaklyactiveactive carboyacycarboyacyllprolines byprolines by

replacement of their terminalreplacement of their terminalcarboylic acid groupcarboylic acid group#which is only a#which is only aweak ligand for forming complees withweak ligand for forming complees with

metals% by a thiol group.metals% by a thiol group.

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!he introduction of thiourea and!he introduction of thiourea andthioamide groups isthioamide groups is usually avoidedusually avoidedbecause these groups may producebecause these groups may produce

goitre, which is a swelling on the neckgoitre, which is a swelling on the neckdue to enlargement of the thyroiddue to enlargement of the thyroidgland.gland.

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2.8.8 hanging the 4isting ubstituents2.8.8 hanging the 4isting ubstituents


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04/12/1604/12/16 prof. azaprof. aza 132132

g g gof a &eadof a &ead

Analogues can also be formed byAnalogues can also be formed byreplacing an eisting substituent inreplacing an eisting substituent in

the structure of a leadthe structure of a lead by a newby a newsubstituent group.substituent group.!he choice of group will depend on!he choice of group will depend on

the ob(ectives of the design team.the ob(ectives of the design team.

It is oftenIt is often made using the conceptmade using the conceptof isosteres.of isosteres.


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Isosteres areIsosteres aregroups that ehibitgroups that ehibitsome similarities in their chemicalsome similarities in their chemicaland*or physical properties.and*or physical properties.

As a result, they can ehibit similarAs a result, they can ehibit similarpharmacokinetic andpharmacokinetic and

pharmacodynamic properties.pharmacodynamic properties.

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In other words, the replacement of aIn other words, the replacement of a

substituent by its isostere is more likelysubstituent by its isostere is more likelyto result in the formationto result in the formation oof an analoguef an analoguewith the same type of activity as thewith the same type of activity as the

lead than the totally random selectionlead than the totally random selectionof an alternative substituent.of an alternative substituent.

'owever, luck still plays a part and an'owever, luck still plays a part and an

isosteric analogueisosteric analogue may have a totallymay have a totallydifferent typedifferent type of activity from its lead.of activity from its lead.

04/12/1604/12/16 prof. azaprof. aza 134134

Tab(e 2.3. amp(es of bioisosteres. ach horizo%ta( ro* represe%ts a

#ro"p of str"ct"res that are isosteric.


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#ro"p of str"ct"res that are isosteric.

identical outer shells of electronsidentical outer shells of electrons


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04/12/1604/12/16 prof. azaprof. aza 136136

lassical isosteres were originally defined bylassical isosteres were originally defined by4rlenmeyer as being atoms, ions and molecules4rlenmeyer as being atoms, ions and moleculesthat had identical outer shells of electronsthat had identical outer shells of electrons..

!his definition has now been broadened to!his definition has now been broadened toinclude groups that produce compounds thatinclude groups that produce compounds thatcan sometimescan sometimes have similar biologicalhave similar biologicalactivitiesactivities#!able 2.8%. !hese groups are#!able 2.8%. !hese groups are

frequently referred to as bioisosteres infrequently referred to as bioisosteres inorder to distinguish them from classicalorder to distinguish them from classicalisosteres.isosteres.


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04/12/1604/12/16 prof. azaprof. aza 137137

A large number of drugs have beenA large number of drugs have beendiscovered by isosteric and bioisostericdiscovered by isosteric and bioisostericinterchanges.interchanges.

$or eample, the replacement of the 7"$or eample, the replacement of the 7"

hydroy group of hypoanthine by a thiolhydroy group of hypoanthine by a thiolgroup gavegroup gave the antitumour drug 7"the antitumour drug 7"mercaptopurinemercaptopurine whereas the replaccrnentwhereas the replaccrnentof hydrogen in the 6"position of uracil bof hydrogen in the 6"position of uracil byy

fluorine resulted influorine resulted in ffluorouracilluorouracil which iswhich isalso an antitumour agent.also an antitumour agent.


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'owever, not all isosteric changes yield'owever, not all isosteric changes yieldcompounds with the same type ofcompounds with the same type ofactivity; the replacement of the;activity; the replacement of the;

"" of the neuroleptic phenothia3ine"" of the neuroleptic phenothia3inedrugs by either ?''" or 'drugs by either ?''" or '22''22""produces the diben3a3epines, whichproduces the diben3a3epines, whichehibit antidepressant activity #$igureehibit antidepressant activity #$igure

2.5%.2.5%.

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2.5. 4amples of drugs discoveredby isosteric replacement

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Drug Discovery by Design