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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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