DrugsynthesisII LkeainesynteesitII Tapio Nevalainen School of Farmacy 2011

Drugdiscoveryprocess

DrugDiscovery
Drugdiscoveryistheprocessbywhichdrugsare discoveredand/ordesigned. Inthepastmostdrugshavebeendiscoveredeitherby identifyingtheactiveingredientfromtraditional remediesorbyserendipitousdiscovery. Anewapproachhasbeentounderstandingdiseaseat themolecularandphysiologicallevelandtotarget specificentities,usuallyproteinreceptorthatis specificallyassociatedwithadiseasecondition(target baseddrugdiscovery).

DrugDiscovery

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

Compounddesigncycle
Identificationofaleadcompoundwithdesiredbiological activity
ORFANIC CHEMISTRY Target Molecule (TM) New TM identif ied Test results Structure-activity relationships (SARs) MEDICINAL CHEMISTRY

Synthesis of TM

Biological evaluation

Candidate for development

Drugdiscovery:findingalead
Chooseadisease! Chooseadrugtarget gtargets g areusually yp proteins, ,sometimesnucleicacids Drug
TARGET EnzymeInhibitor Receptor* Nucleicacid MECHANISM reversibleorirreversible Agonist or antagonist Intercalator (binder), modifier (alkylating agent) orsubstratemimic. Blockersoropeners Uptake inhibitors

Ionchannels* Transporters*
*Present in the cell membranes

Newdrugtargets
Only 483targets accountforalldrugsonthemarket.
45%ofthesearecellmembranereceptors,28%enzymes,hormones (11%),ionchannels(5%),nuclearreceptors(2%)andDNA(2%).About 7%ofthetargetsarenotknownbiochemically.

Ofthe30000humangenes,onlyaminoritymightturnouttobe interestingdrugtargets.Therehavebeenestimatesthatthenumber ofthesetargetswouldrangefrom3000to10000.

TRENDS in Biotechnology Vol.19 No.12 December 2001

Newdrugtargets

Number of released entries

TheOmicsRevolution

Year

CourtesyoftheRCSBProteinDataBank

Drugdiscovery:Findingalead
Choiceofbioassay invitro/invivo
i invitro it ofirst: fi st cheaper, cheape easier easie tocarry ca yout, out lesscontroversial, co t o e sial can ca be automated druginteractionswithspecifictarget,pharmacokineticsproperties. transgenicanimals

Highthroughputscreening ScreeningbyNMR Affinityscreening Testvalidity

Sometimeseasyandclear:antibacterials,localanaesthetics. Inothercasesdifficult:antipsychoticdrugs

Findingaleadcompound
Screeningofnaturalproducts
H

H O H

O O O NH O O OH paclitaxel

O O

OO O

OH

fermentation(antibiotics) Artemisinin plantextracts(anticanceragents) Chemicalmodificationofnaturalproducts(semisynthesis)

HO O O O O

Screeningsyntheticcompoundlibraries
75%ofdrugsaresyntheticchemicals

Findingaleadcompound
Chemical modification ofexisting drugs
Captopril andmetoodrugs

Starting from thenatural ligand or modulator compounds

Salbutamol andisoprenaline arederivedfromadrenalin

Newtechnologiestofindaleadcompounds
Combinatorialandparallelsynthesis
Compoundmixturesorsinglecompounds Solidphasesynthesis

Computeraideddesignofleadcompounds Computerizedsearchingofstructuraldatabases Fragmentbasedleaddiscovery

basedonidentifyingsmallchemicalfragments,whichmaybindonly weaklytothebiologicaltarget target,andthengrowingthemorcombining themtoproducealeadwithahigheraffinity.

Fragmentbasedleaddiscovery
DesignofaligandCfortheFK506bindingproteinusingNMR spectroscopy.Fragments(AandB)boundtodifferentregions. StructureCwithpropyllinkhadhigheraffinity.
O N H HO A Kd = 100 M O OH O O B Kd = 2 M MeO M O MeO OMe N OH O O O O O N H HO C Kd = 0.049 M OH

N MeO MeO OMe

Fragmentselfassembly
Form of dynamic combinatorial chemistry - Click chemistry in situ
Acetylcholinesterase as a template for the reaction of acetylene and azide building blocks, the syn addition product was the only compound formed and turned out to be the strongest noncovalent inhibitor of acetylcholinesterase yet identified.

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

Isolation,purificationandstructure determinationofleadcompounds
Isolation andpurification
Extraction E t actio Crystallization Chromatography Freezedrying

Structure determination
NMRspectroscopy
LargevarietyofNMRexperiments:1H,13C,2D,

Massspectrometry Elementalanalysis IRspectroscopy Xraycrystallography

Synthesisofleadcompounds
Today,achemisttypicallysuppliesnewcompoundsto thescreenerinmilligramamounts Onechemistsynthesizes,purifies,andcharacterizes about100novelcompoundsperyear Ittakesapproximately10,000differentcompoundsto developadrugthatwillmakeittomarket

Drugdesign(leadoptimization)
Identifystructureactivityrelationships(SARs).
Ligandorstructurebased

Identifythepharmacophore. Improvetargetinteractions(pharmacodynamics).
Receptorbinding,effectsonthebody,therapeutic window,undesirableeffects

Improve p p pharmacokineticproperties p p .
ADME(absorption,distribution,metabolism,and excretion)

Propertiesofleadcompounds LipinskisRuleofFive
IfALLParameters Are LogP HBondDonors HBondAcceptors MolecularWeight LIPINSKI PREDICTION FORACOMPOUND IfANYParameter Is

5 5 10 500
GOODAbsorption or Permeation

>5 >5 >10 >500

POORAbsorption orPermeation

Compound classes that are substrates for biological transporters are exceptions 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
InhibitionofHERGpotassiumionchannelsinthe h t heart.
Thegastricagentcisapridehadtobewithdrawnfrom H2N themarketbecauseofthisproblem.
Cl HN O N cisapride O F O O

Amestest
todetectpotentialmutagenicityorcarcinogenicityin newcompounds.

Drugdevelopment
Patent thedrug
Coverastructuralclassofcompounds.Asignificantperiodof thepatentislostasaresultofthetimetakentogetadrugto themarket.

Carry outpreclinical trials (drug metabolism, toxicology,formulation andstability tests, pharmacology studies etc). Designamanufacturing process (chemical andprocess development). p ) Carry outclinical trials. Register andmarket thedrug. Make money

Drugdiscoveryanddevelopmentisalongand anexpensiveprocess
Thetimefromconceptiontoapprovalofanewdrugistypically10 15years Apatentgrants20yearsprotectiontotheholder Thevastmajorityofmoleculesfailalongtheway:1outof1525 drugcandidatessurvivesthedetailedsafetyandefficacytesting Theestimatedcosttobringtomarketasuccessfuldrug(new chemicalentityorNCE)isabout1billionUSD HighcostsconsistofR&Dcosts,extensiveclinicaltestingand safetymonitoring

10

Expensesandrevenuescurveforanew drug

Patent expires +$ Marketing approval Revenues

5 -$ Expences

10

15

20

Ti Time

Newmolecularentitiesandbiologiclicenseapplications approvedbytheUSFDAbyyear

Nature Reviews Drug Discovery 7, 107-109 (February 2008)

11

Mercksstockplunged40% afterwithdrawalofCOX2 inhibitorrofecoxib(Vioxx)

Rofecoxib (Vioxx Vioxx) ) A nonsteroidal anti anti-inflammatory drug Treatment for osteoarthritis, acute pain conditions, and dysmenorrhoea Cause increased risk of heart attack and stroke with long long-term, highhighdosage use leading it to be withdrawn 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 (Ratiopharm GmbH)

Companycode:

SR141716(Rimonabant,Acomplia)

12

HN

Topdrugproductsbysales
F

N O HO HO atorvastatin Lipitor
-O

Advair Diskus O HO H OH H F O F H fluticasone salmeterol Na+ OO H H O S F HO HO N H OH

S Cl O O Cl N O HO S OH O Plavix clopidogrel S Singulair montelukast H3C HO N

CH3

Enbrel (etanercept) is recombinant-DNA drug

Aranesp (darbepoetin alfa) and Epogen (epoetin alfa) are synthetic erythropoietins

Threemainissuesareinvolvedindrug development
1. Thedrughastobetestedtoensurethatitisnotonly safeandeffective, effective butcanbeadministeredina suitablefashion.Thisinvolvespreclinicaland clinicaltrialscoveringtoxicity,drugmetabolism, stability,formulation,andpharmacologicaltests. 2. Patentaretakenoutassoonasausefuldrughas beenidentified. 3. The 3 ed drug ughas astobesy synthesized t esi edi ine ever e i increasing c easi g quantitiesfortestingandeventualmanufacture(this isknownaschemicalandprocessdevelopment).

26

13