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MedicinalChemistry&
DrugDiscoveryDr.PeterWipfDepartmentofChemistryUniversityofPittsburgh/wipf/index.html/wipf/Courses.html•Surveyofcurrentdrugs•Drugdiscoverychallenges•Methodstoidentifynewleads•Casestudiesfromindustry•Forwardchemicalgenetics-reverse pharmacologyMedicinalChemistryThesciencethatdealswiththediscoveryordesignofnewtherapeuticagentsandtheirdevelopmentintousefulmedicines.Itinvolves:SynthesisStructure-ActivityRelationships(SAR)
Receptorinteractions
Absorption,distribution,metabolism,andexcretion(ADME)2003BlockbustersattheDrugstore(US/Worldwide;outof~$500b)Lipitor(Pfizer)cholesterol$6.8/10.3billion(66%)Zocor(Merck)cholesterol$4.4/6.1billion(72%)Zyprexa(EliLilly)antipsychotic$3.2/4.8billion(72%)Norvasc(Pfizer)bloodpressure$2.2/4.5billion(40%)Procrit(J&J)anemia$3.3/4.0billion(83%)Prevacid(TAP)ulcers$4.0/4.0billion(100%)Nexium(AstraZeneca)ulcers$3.1/3.8billion(82%)Plavix(BMS-Sanofi)bloodthinner$2.2/3.7billion(59%)Seretide(GSK)asthma$2.3/3.7billion(62%)Zoloft(Pfizer)depression$2.9/3.4billion(85%)Epogen(Amgen)anemia$3.1/?billion(?%)Celebrex(Pfizer)arthritis$2.6/?billion(?%)Source:IMSHealth,March2004“BigPharma”DrugDiscoveryinthe21stCenturyTheProblem:Thepharmaceuticalindustryisshortofnewdrugs.Inthe2ndpartof the20thcentury,about50-60newdrugs(NCEs)wereapprovedby theFDAeveryyear.Incontrast,in2002,ahistoricallowof18 NCEswereapproved(in2001,24NCEs,in2000,27NCEs,in 2003,21NCEs). Conversely,researchcostsforanewdrugare estimatedtobeinthe$1-1.5Bi.range.Consideringallhigh-profile failuresinrecentdrugdiscovery,thisfigureisunlikelytodrop substantially.
Source:WallStreetJ.11/21/2003“…gloomaroundthepharmaceuticalscompany..”Source:WallStreetJ.2/24/2004Wallstreet(andcompanies)arelookingforascapegoat..”DrugIndustry'sBigPushIntoTechnologyFallsShort.TestingMachinesWereBuiltToStreamlineResearch--ButMayBeStiflingIt“Adecadeago,pharmaceuticalcompaniesannouncedarevolutionarynewwayoffindingdrugs.Insteadofrelyingonscientists'hunchesaboutwhatchemicalstoexperimentwith,theybroughtinmachinestocreatethousandsofchemicalcombinationsatonceandtestedthemoutwithrobots.Thenewtechnologywassupposedtobringafloodofmedicinestopatientsandprofitstoinvestors.Today,someleadingchemistsarecallingtheeffortanexpensivefiasco.Machineschurnedoutchemicalafterchemicalthatdidn'tproduceusefulresults.Andchemicalsthatseemedpromisingoftenturnedouttohavebigflawsthattraditionaltestingmighthavecaughtearlieron.Somedrugscouldn'tdissolveinwaterorbeturnedintopills,forexample.Criticsbelievetheseproblemshelpexplainthepharmaceuticalindustry'sdroughtofnewproducts."That'sthesecretofwhythey'respendingbillionsofdollarsandgettingnothing,"saysJamesHussey,aformerBristol-MyersSquibbCo.managerwhonowleadsbiotechcompanyNeoPharmInc.…..”InSearchofNewLeads…..Thedeclineinthenumberofnewdrugsisbased,amongotherreasons,onthecurrenthightherapeuticstandardinmanyindications,focusingresearchonchronicdiseasessuchascoronaryheart,Alzheimer’s,arthritis,cancer,andAIDS,aswellastheenhancedregulatoryrequirementsforefficacyandsafetyofnewdrugs.Aleadcanbecharacterizedasacompoundthathassomedesirablebiologicalactivity,notextremelypolarorlipophilic,andnotcontaintoxicorreactivefunctionalgroups.Often,molecularweight(<350)andlipophilicity(logP<3)areconsideredthemostobviouscharacteristicsofadrug-likelead.Theleadshouldalsohaveaseriesofcongenersthatmodulatebiologicalactivity,indicatingthatfurtherstructuralmodificationwillimproveselectivityandpotency.If10,000chemistsweretoprepare1compoundeachpersecond,itwouldtake10,000,000,000,000,000,000,000,000,000yearstofinishthejob.WhyIsItSoDifficulttoMakeDrugs?DrugDiscoveryParadigmChemistry-drivendrugdiscovery-backtothefuture?Currently:Biology-drivendrugdiscoveryWhereDid(Do)OurDrugsComeFrom?NewdrugsfromoldpoisonsThereductionistapproachtomedicinebeganwiththeisolationofopiumalkaloidsMedicinalChemistryFolkloreEarliestmedicines 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