1 Drug Discovery

8/4/2019 1 Drug Discovery

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DrugsynthesisIILkeainesynteesitII

Tapio NevalainenSchool of Farmacy2011

Drugdiscoveryprocess

DrugDiscovery

Drugdiscoveryistheprocessbywhichdrugsarediscoveredand/ordesigned.

Inthepastmostdrugshavebeendiscoveredeitherbyidentifyingtheactiveingredientfromtraditional

remediesorbyserendipitousdiscovery.Anewapproachhasbeentounderstandingdiseaseat

themolecularandphysiologicallevelandtotarget,

specificallyassociatedwithadiseasecondition(targetbaseddrugdiscovery).


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DrugDiscovery

Angew. Chem. Int. Ed. 2001, 40, 18,3341

Compounddesigncycle

Identificationofaleadcompoundwithdesiredbiologicalactivity

CHEMISTRY CHEMISTRY

Target

Molecule(TM)

Synthesisof TM

New TM

identified

Test resultsStructure-activityrelationships (SARs)

Biologicalevaluation

Candidate fordevelopment


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Drugdiscovery:findingalead

Chooseadisease!

Chooseadrugtarget

Dru tar etsareusuall roteins,sometimesnucleicacids

TARGET MECHANISM

EnzymeInhibitor reversibleorirreversible

Receptor* Agonist or antagonist

Nucleicacid Intercalator (binder),modifier (alkylating agent)orsubstratemimic.

*Present in the cell membranes

Ionchannels* BlockersoropenersTransporters* Uptake inhibitors

Newdrugtargets

Only 483targets accountforalldrugsonthemarket.

45%ofthesearecellmembranereceptors,28%enzymes,hormones(11%),ionchannels(5%),nuclearreceptors(2%)andDNA(2%).About7%ofthetargetsarenotknownbiochemically.

Ofthe30000humangenes,onlyaminoritymightturnouttobeinterestingdrugtargets.Therehavebeenestimatesthatthenumberofthesetargetswouldrangefrom3000to10000.

TRENDS in Biotechnology Vol.19 No.12 December 2001


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Newdrugtargets

mberofreleasedentries

N

u

YearTheOmicsRevolution CourtesyoftheRCSBProteinDataBank

Drugdiscovery:Findingalead

Choiceofbioassay

invitro/invivo

nv ro rs :c eaper,eas er ocarryou , esscon rovers a ,can eautomated

druginteractionswithspecifictarget,pharmacokineticsproperties.transgenicanimals

Highthroughputscreening

ScreeningbyNMR

Affinityscreening

Testvalidity

Sometimeseasyandclear:antibacterials,localanaesthetics.

Inothercasesdifficult:antipsychoticdrugs


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FindingaleadcompoundScreeningofnaturalproducts

fermentation(antibiotics)

lant extracts anticancer a ents

O

O

O

O OH

H

H

Artemisinin

O

O

OO

OH

OOHO

NH

OH

OO

O

O

Chemicalmodificationofnaturalproducts(semisynthesis)

O

75%ofdrugsaresyntheticchemicals

Findingaleadcompound

Chemical modification ofexisting drugs

Captopril and metoo drugs

Starting from thenatural ligand or modulator compounds

Salbutamol andisoprenaline arederivedfromadrenalin


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Newtechnologiestofindaleadcompounds

Combinatorialandparallelsynthesis

Compoundmixturesorsinglecompounds

Solidphasesynthesis

Computeraideddesignofleadcompounds

Computerizedsearchingofstructuraldatabases

Fragmentbasedleaddiscovery

basedonidentifyingsmallchemicalfragments,whichmaybindonlywea y o e o og ca arge ,an engrow ng emorcom n ngthemtoproducealeadwithahigheraffinity.

Fragmentbasedleaddiscovery

DesignofaligandCfortheFK506bindingproteinusingNMRspectroscopy.Fragments(AandB)boundtodifferentregions.StructureCwithpropyllinkhadhigheraffinity.

NH

OHO

HO

O

O

N O

OMeO

C

Kd = 0.049 M

NH

OHO

HO

OH

O

A

Kd = 100 M

e

OMeN O

OMeO

MeO

OMe

B

Kd = 2 M


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Fragment selfassembly Form of dynamic combinatorial chemistry - Click chemistry in situ

Acetylcholinesterase as atemplate for the reaction ofacetylene and azide buildingblocks, the syn additionproduct was the onlycompound formed andturned out to be thestrongest noncovalentinhibitor ofacetylcholinesterase yetidentified.

http://pubs.acs.org/cen/coverstory/8006/8006clickchemistry.html

Isolation,purificationand structuredeterminationofleadcompounds

Isolation andpurification

Extraction

Crystallization

Chromatography

Freezedrying

Structure determination

NMRspectroscopy

LargevarietyofNMRexperiments:1H,13C,2D,

Massspectrometry

Elementalanalysis

IRspectroscopy

Xraycrystallography


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Synthesisofleadcompounds

Today,achemisttypicallysuppliesnewcompoundstothescreenerinmilligramamounts

Onechemistsynthesizes,purifies,andcharacterizesabout100novelcompoundsperyear

Ittakesapproximately10,000differentcompoundstodevelopadrugthatwillmakeittomarket

Drugdesign(leadoptimization)

Identifystructureactivityrelationships(SARs).

Identifythepharmacophore.

Improvetargetinteractions(pharmacodynamics).

Receptorbinding,effectsonthebody,therapeuticwindow,undesirableeffects

Im rove harmacokinetic ro erties.

ADME (absorption,distribution,metabolism,andexcretion)


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Propertiesofleadcompounds

LipinskisRuleofFiveIfALLParametersAre

IfANYParameterIs

LogP 5 >5

HBondDonors 5 >5

HBondAcceptors 10 >10

MolecularWeight 500 >500

LIPINSKIPREDICTIONFORACOMPOUND

GOODAbsorptionorPermeation

POORAbsorptionorPermeation

Compound classes that are substrates for biological transporters areexceptions to the rule. Reference: Adv. Drug Delivery Rev., 1997,23(1-3), 3-25.

On-line calculation of drug-relevant properties:molinspiration: http://www.molinspiration.com/OSIRIS Property Explorer: http://www.organic-chemistry.org/

Earlytestsforpotentialtoxicity

InhibitionofHERGpotassiumionchannelsintheeart.

Thegastricagentcisapridehadtobewithdrawnfromthemarketbecauseofthisproblem.

Amestest

to detect otential muta enicit or carcino enicit in

O

HN

ON O

F

Cl

H2N O

cisapride

newcompounds.


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DrugdevelopmentPatent thedrug

Coverastructuralclassofcompounds.Asignificantperiodofthepatentislostasaresultofthetimetakentogetadrugtothemarket.

Carry outpreclinical trials (drug metabolism,toxicology,formulation andstability tests,pharmacology studies etc).

Designamanufacturing process (chemical andprocessdevelopment).

Carry outclinical trials.

Register andmarket thedrug.

Make money

Drugdiscoveryanddevelopmentisalongandanexpensiveprocess

Thetimefromconceptiontoapprovalofanewdrugistypically10

Apatentgrants20yearsprotectiontotheholder

Thevastmajorityofmoleculesfailalongtheway:1outof1525

drugcandidates

survives

the

detailed

safety

and

efficacy

testing

Theestimatedcosttobringtomarketasuccessfuldrug(newchemicalentityorNCE)isabout1billionUSD

HighcostsconsistofR&Dcosts,extensiveclinicaltestingand


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Expensesandrevenuescurveforanewdrug

+$ Revenues

Patentexpires

Marketingapproval

-$

5 10 15 20Expences

me

Newmolecularentitiesandbiologiclicenseapplications

approvedbytheUSFDAbyyear

Nature Rev iews Dru g D iscovery 7, 107-109 (February 2008)


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Mercksstockplunged40% afterwithdrawalofCOX2

inhibitorrofecoxib(Vioxx)

RofecoxibRofecoxib ((VioxxVioxx)) AA nonsteroidalnonsteroidal antianti--inflammatoryinflammatory

drugdrug Treatment for osteoarthritis acuteTreatment for osteoarthritis acute

pain conditions, and dysmenorrhoeapain conditions, and dysmenorrhoea Cause increased risk of heart attackCause increased risk of heart attack

and stroke with longand stroke with long--term, highterm, high--dosage use leading it to bedosage use leading it to bewithdrawn from marketwithdrawn from market

Drug names

Chemical name 2[4(2methylpropyl)phenyl]propanoic acid

Generic name ibuprofen

Tradename(s)or Brandname(s) Burana (Orion),Brufen retard (Abbott),Ibusal (Orion),Ibuxin (Merckle),Ibumax (Vitabalans),Ibumetin(Nycomed),IbuprofenRatiopharm (RatiopharmGmbH)

Companycode: SR141716(Rimonabant,Acomplia)


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TopdrugproductsbysalesN

O

-O

HNO

HO HO

FatorvastatinLipitor

H

O

F

HO

H

HO

F H

OH

H

S F

fluticasone

OHHO

NH

O

HO

salmeterol

Advair Diskus

O S

N

S

O

O-

Cl

Na+

O

N

ClS

O

OHO OH

Plavixclopidogrel

Singulair

montelukast CH3

3

HO

Enbrel (etanercept) is recombinant-DNA drug Aranesp (darbepoetin alfa) andEpogen (epoetin alfa) are synthetic erythropoietins

Threemainissuesareinvolvedindrugdevelopment

1. Thedrughastobetestedtoensurethatitisnotonly,

suitablefashion.Thisinvolvespreclinicalandclinicaltrialscoveringtoxicity,drugmetabolism,

stability,formulation,

and

pharmacological

tests.

2. Patentaretakenoutassoonasausefuldrughasbeenidentified.

3. Thedru hastobes nthesizedineverincreasin quantitiesfortestingandeventualmanufacture(thisisknownaschemicalandprocessdevelopment).

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1 Drug Discovery