药物发现和发展培训课件

药药物物发现发现和和发发展展IntroductionInthepastmostdrugshavebeendiscoveredeitherbyidentifyingtheactiveingredientfromtraditionalremediesorbyserendipitousdiscovery.Butnowweknowdiseasesarecontrolledatmolecularandphysiologicallevel.Alsoshapeofanmoleculeatatomicleveliswellunderstood.InformationofHumanGenome2药物发现和发展3药物发现和发展Registration:TheMinistryofhealth&FamilyWelfareandtheMinistryofChemicals&FertilizershavemajorroleinregulationofIPM.NDAmustbesubmittedtoDCGIPhaseIIIstudyreportedtoCDL,KolkataPackageinsertedapprovedbyDCIMarketingapprovalfromFDA4药物发现和发展$800Mspenttobringanewdrugtomarket.$127BillionspentonPharmaR&Din2010ShareofCROsinresearchoperationsis27%WorldCROmarketis16.3B(Indianshare$500M)MarketScenerio:5药物发现和发展TopCROs(ByRevenue)ContractResearchOrganizationsRevenueQuintiles$2.5BillionPharmaceuticalProductDevelopment$1.8BillionCovance$1.4BillionCharlesRiverLaboratories$1.2BillionParexel$930MillionIcon$887MillionKendle$590MillionPharmanet$470MillionPRAInternational$410Million4GPharmacovigilance$391Million6药物发现和发展TopCROs(India)ContractResearchOrganizationsLocationActimusBiosciencesHyderabadAdvinusTherapeuticsBangaloreAurigeneDiscoverytechnologiesBangaloreChembiotekKolkataGVKBiosciencesHyderabadJubilantOrganosysBangaloreRanbaxyLifeSciencesMumbaiRelianceLifeSciencesMumbaiSuvenLifeSciencesHyderabadSyngeneBangalore7药物发现和发展MostvaluableR&DProjectsRankProductCompanyPhasePharmacologicalclassTodaysNPV($mn)1DegludecNovoNordiskPhaseIIIInsulin5,8072TofacitinibPfizerPhaseIIIJAK-3inhibitor4,9533BG-12BiogenIdecPhaseIIIFumarate4,6664IncivekJ&JPhaseIVHepCproteaseinhibitor4,3325RelovairTheravancePhaseIIICorticosteroid4,2416DRCysteamineUndisclosedPhaseIIILysosomaltransportmodulator4,1557AMR101UndisclosedPhaseIIIOmega-3fattyacid4,0528EliquisBristolMyersSquibb PhaseIVFactorXainhibitor3,8369EliquisPfizerPhaseIVFactorXainhibitor3,59210BexsseroNovartisPhaseIVMeningococcalBvaccine3,2508药物发现和发展TopCompaniesbyR&DExpense:Sr.No.CompanyR&D spend($bn),20101Novartis7.92Merck&Co8.13Roche7.84GlaxoSmithKline5.75Sanofi5.86Pfizer9.17Johnson&Johnson4.58EliLilly4.79AstraZeneca4.210Takeda3.411Bayer2.312Bristol-MyersSquibb3.313BoehringerIngelheim3.114Amgen2.815NovoNordisk1.79药物发现和发展DrugDevelopmentCostBreak-upR&DFunction%Discovery/Basic ResearchSynthesis&Extraction10.0BiologicalScreening&testing14.2Preclinical TestingToxicology&Safetytesting4.5PharmaceuticalDosageFormulation7.3Clinical TrialsPhaseI,II,III29.1PhaseIV11.7Manufacturing&QC8.3IND&NDA4.1Bioavailability1.8Others9.0Total100.010药物发现和发展10,000COMPOUNDS250COMPOUNDS5COMPOUNDS1FDAAPPROVEDDRUG6.5 YEARS7 YEARS1.5 YEARSDRUG DISCOVERYPRECLINICALCLINICAL TRIALSFDAREVIEWDrug Discovery&Development-Timeline11药物发现和发展DrugDiscoveryDrugsDiscoverymethods:RandomScreeningMolecularManipulationMolecularDesigningDrugMetabolitesSerendipity12药物发现和发展13药物发现和发展Target SelectionTargetselectionindrugdiscoveryisdefinedasthedecisiontofocusonfindinganagentwithaparticularbiologicalactionthatisanticipatedtohavetherapeuticutilityisinfluencedbyacomplexbalanceofscientific,medicalandstrategicconsiderations.Targetidentification:toidentifymoleculartargetsthatareinvolvedindiseaseprogression.Targetvalidation:toprovethatmanipulatingthemoleculartargetcanprovidetherapeuticbenefitforpatients.14药物发现和发展Target SelectionBiochemicalClassesofDrugTargetsG-proteincoupledreceptors-45%enzymes-28%hormonesandfactors-11%ionchannels-5%nuclearreceptors-2%TechniquesforTargetIdentification15药物发现和发展Cellular&GeneticTargets:Involvestheidentificationofthefunction of a potential therapeuticdrugtargetanditsroleinthediseaseprocess.Forsmall-moleculedrugs,thisstepintheprocess involves identification of thetarget receptorsor enzymes whereasfor some biologic approaches thefocus is at the gene or transcriptionlevel.Drugs usually act on either cellular orgeneticchemicalsinthebody,knownas targets,which are believed to beassociatedwithdisease.16药物发现和发展Cellular&GeneticTargets:Scientistsuseavarietyoftechniquestoidentify and isolate individual targetsto learn more about their functionsandhowtheyinfluencedisease.Compoundsarethenidentifiedthathavevarious interactions with the drugtargets that might be helpful intreatmentofaspecificdisease.17药物发现和发展Genomics:The study of genes and their function.Genomics aims to understand thestructure of the genome,including themappinggenesandsequencingtheDNA.Seeks to exploit the findings from thesequencing of the human and othergenomestofindnewdrugtargets.HumanGenomeconsistsofasequenceofaround3billionnucleotides(theACGTbases)whichinturnprobablyencode35,00050,000genes.18药物发现和发展Genomics:Drews estimates that the number of genesimplicatedindisease,boththoseduetodefectsin single genes and those arising fromcombinationsofgenes,isabout1,000Based on 5 or 10 linked proteins per gene,heproposes that the number of potential drugtargetsmayliebetween5,000and10,000.Single Nucleotide Polymorphism(SNP)libraries:areusedtocomparethegenomesfrombothhealthyandsickpeopleandtoidentifywheretheirgenomesvary.19药物发现和发展Proteomics:Itisthestudyoftheproteome,thecompletesetof proteinsproduced by a species,usingthe technologies of large scale protein separation andidentification.Itisbecomingincreasinglyevidentthatthecomplexityofbiologicalsystems lies at the levelofthe proteins,and that genomicsalonewillnotsufficetounderstandthesesystems.Itisalsoattheproteinlevelthatdiseaseprocessesbecomemanifest,and at which most(91%)drugsact.Therefore,theanalysisofproteins(includingprotein-protein,protein-nucleicacid,andproteinligandinteractions)willbeutmost importance to targetdiscovery.20药物发现和发展Proteomics:Proteomicsisthesystematichigh-throughputseparationandcharacterizationofproteinswithinbiologicalsystems.Target identification with proteomics isperformed by comparing the proteinexpression levels in normal and diseasedtissues.2D PAGE is used to separate the proteins,whicharesubsequentlyidentifiedandfullycharacterizedwithLC-MS/MS.21药物发现和发展Bioinformatics:Bioinformaticsisabranchofmolecularbiologythatinvolvesextensiveanalysisofbiologicaldatausingcomputers,forthepurposeofenhancingbiologicalresearch.Itplaysakeyroleinvariousstagesofthedrugdiscoveryprocessincludingtargetidentificationcomputerscreeningofchemicalcompoundsandpharmacogenomics22药物发现和发展Bioinformatics:Bioinformatics methods are used totransform the raw sequence intomeaningfulinformation(eg.genesandtheirencodedproteins)andtocomparewholegenomes(diseasevs.not).Can compare the entire genome ofpathogenicandnon-pathogenicstrainsofamicrobeandidentifygenes/proteinsassociatedwithpathogenismUsinggeneexpressionmicroarraysandgenechiptechnologies,asingledevicecanbeusedtoevaluateandcomparetheexpressionofupto20000genesofhealthy and diseased individuals atonce23药物发现和发展Lead Discovery:IdentificationofsmallmoleculemodulatorsofproteinfunctionTheprocessoftransformingtheseintohigh-contentleadseries.24药物发现和发展SynthesisandIsolation:SeparationofmixtureSeparationofimpuritiesInvitrochemicalsynthesisBiosyntheticintermediate25药物发现和发展CombinatorialChemistry:Rapidsynthesisoforcomputersimulationoflargeno.ofdifferentbutstructurallyrelatedmoleculesSearchnewleadsOptimizationoftargetaffinity&selectivity.ADMEpropertiesReducetoxicityandeliminatesideeffects26药物发现和发展AssayDevelopmentUsedformeasuringtheactivityofadrug.Discriminatebetweencompounds.Evaluate:Expressedproteintargets.Enzyme/substrateinteractions.27药物发现和发展Highthroughputscreening:Screeningofdrugtargetagainstselectionofchemicals.Identificationofhighlytargetspecificcompounds.28药物发现和发展Highthroughputscreening:29药物发现和发展Medicinal Chemistry:Itsadisciplineattheintersectionofsyntheticorganicchemistryandparmacology.Focusesonsmallorganicmolecules(andnotonbiologicsandinorganiccompounds)UsedinDrugdiscovery(hits)Leadoptimization(hittolead)Processchemistryanddevelopment30药物发现和发展LibraryDevelopment:Collectionofstoredchemicalsalongwithassociateddatabase.AssistsinHighThroughputScreeningHelpsinscreeningofdrugtarget(hit)Basedonorganicchemistry31药物发现和发展SARStudies:HelpsidentifypharmacophoreThepharmacophoreistheprecisesectionofthemoleculethatisresponsibleforbiologicalactivityEnablestopreparemoreactivecompoundAlloweliminationofexcessivefunctionality32药物发现和发展SARStudies:MorphineMolecule33药物发现和发展Insilicoscreening:ComputersimulatedscreeningofchemicalsHelpsinfindingstructuresthataremostlikelytobindtodrugtarget.FilterenormousChemicalspaceEconomicthanHTS34药物发现和发展ChemicalSynthesis:Involveproductionofleadcompoundinsuitablequantityandqualitytoallowlargescaleanimalandeventual,extensivehumanclinicaltrialsOptimizationofchemicalrouteforbulkindustrialproduction.Suitabledrugformulation35药物发现和发展In Vitro Studies:(Inglass)studiesusingcomponentoforganismi.e.testtubeexperimentsExamples-CellsderivedfrommulticellularorganismsSubcellularcomponents(Ribosomes,mitochondria)Cellular/subcellularextracts(wheatgerm,reticulocyteextract)Purifiedmolecules(DNA,RNA)36药物发现和发展In Vitro Studies:Advantages:Studiescanbecompletedinshortperiodoftime.Reducesriskinpostclinicaltrialspermitsanenormouslevelofsimplificationofthesysteminvestigatorcanfocusonasmallnumberofcomponents37药物发现和发展DrugaffinityandselectivityDrug affinityistheabilityofdrugtobindtoitsbiologicaltarget(receptor,enzyme,transportsystem,etc.)Selectivity-Drugshouldbindtospecificreceptorsiteonthecell(eg.Aspirin)38药物发现和发展Isogenic human disease models-areafamilyofcellsthatareselectedorengineeredtoaccuratelymodelthegeneticsofaspecificpatientpopulation,invitroStem cell disease models-Adultorembryonicstemcellscarryingorinducedtocarrydefectivegenescanbeinvestigatedin vitro tounderstandlatentmolecularmechanismsanddiseasecharacteristicsCelldiseasemodels39药物发现和发展OptimizingchemicalhitsforclinicaltrialiscommonlyreferredtoasleadoptimizationTherefinementinstructureisnecessaryinordertoimprovePotencyOralAvailabilitySelectivitypharmacokineticpropertiessafety(ADMEproperties)LeadCandidaterefinement40药物发现和发展In vivo studiesItsexperimentationusingawhole,livingorganism.Givesinformationabout,MetabolicprofileToxicologyDruginteraction41药物发现和发展AnimalmodelsofdiseasestatesTestconditionsinvolvinginduceddiseaseorinjurysimilartohumanconditions.Mustbeequivalentinmechanismofcause.Canpredicthumantoxicityin71%ofthecases.Eg.SCIDmice-HIVNODmice-DiabetesDaniorerio-Genefunction42药物发现和发展BehaviouralStudiesToolstoinvestigatebehaviouralresultsofdrugs.Usedtoobservedepressionandmentaldisorders.Howeverselfesteemandsuicidalityarehardtoinduce.Example:Despairbased-Forcedswimming/TailsuspensionRewardbasedAnxietyBased43药物发现和发展FunctionalImaging:Methodofdetectingormeasuringchangesinmetabolism,bloodflow,regionalchemicalcomposition,andabsorption.Tracersorprobesused.ModalitiesUsed-MRICT-Scan44药物发现和发展Ex-VivoStudies:Experimentationontissueinanartificialenvironmentoutsidetheorganismwiththeminimumalterationofnaturalconditions.Countersethicalissues.Examples:MeasurementoftissuepropertiesRealisticmodelsforsurgery45药物发现和发展Clinicaltrials:Setofproceduresinmedicalresearchanddrugdevelopmenttostudythesafetyandefficacyofnewdrug.Essentialtogetmarketingapprovalfromregulatoryauthorities.Mayrequireupto7years.46药物发现和发展Phase0:Recentdesignation,alsoknownashumanmicro-dosingstudies.Firstinhumantrials,conductedtostudyexploratoryinvestigationalnewdrug.Designedtotospeedupthedevelopmentofpromisingdrugs.Concernedwith-PreliminarydataonthedrugspharmacodynamicsandpharmacokineticsEfficacyofpre-clinicalstudies.47药物发现和发展PhaseI:ClinicalPharmacologicEvaluationFirststageoftestinginhumansubjects.20-50HealthyVolunteersConcernedWith:HumanToxicity.ToleratedDosageRangePharma-cology/dynamics48药物发现和发展PhaseI:TypesofPhase-ITrialsSAD(SingleAscendingDose)MAD(MultipleAscendingDose)Foodeffect49药物发现和发展PhaseIII:ExtendedClinicalTrials.Mostexpensive&timeconsuming.250-1000Patients.ControlledDoubleBlindTechnique.ConcernedWith:Safety,EfficacyComparisonwithotherDrugsPackageInsert51药物发现和发展PhaseIV:PostMarketingSurveillance.Designedtodetectanyrareorlong-termadverseeffects.AdverseDrugReactionMonitoring.Pharmacovigilance.52药物发现和发展10,000COMPOUNDS250COMPOUNDS5COMPOUNDS1FDAAPPROVEDDRUG6.5 YEARS7 YEARS1.5 YEARSDRUG DISCOVERYPRECLINICALCLINICAL TRIALSFDAREVIEWDrug Discovery&Development-Timeline53药物发现和发展GeneTherapyTechniqueforcorrectingdefectivegenes.Itistheprocessofinsertinggenesintocellstotreatdiseases.Genetherapyisusedtocorrectadeficientphenotype.54药物发现和发展GeneTherapy-ApproachesGermline Gene TherapySpermoreggs,aremodifiedbytheintroductionoffunctionalgenes,whichareintegratedintotheirgenomes.Changewouldbeheritableandwouldbepassedontolatergenerations.Somatic Gene TherapyThetherapeuticgenesaretransferredIntothesomaticcellsofapatient.Changewillnotbeinheritedbythepatientsoffspringorlatergenerations.55药物发现和发展GeneTherapy-TypesEx Vivo Gene TherapyTransferoftherapeuticgenesinculturedcellswhicharethenreintroducedintopatient.Eg:TherapyforADADeficiencyIn Vivo Gene TherapyThedirectdeliveryofgenesintothecellsofaparticulartissueisreferredtoasinvivogenetherapy.Eg:TherapyforCysticfibrosis56药物发现和发展GeneTherapy-VectorsVirusesRetrovirusesAdenovirusesAdeno-associatedvirusesHerpesSimplexvirusesPureDNAConstructsLipoplexesDNAMolecularConjugatesHumanArtificialChromosome57药物发现和发展GeneTherapy-LimitationsShortlivednatureofgenetherapyImmuneresponseProblemswithviralvectorsMultigenedisorders58药物发现和发展RecentDevelopmentsNanotechnology+genetherapyyieldedtreatmenttotorpedocancerResultsofworldsfirstgenetherapyforinheritedblindnessshowsightimprovementNewMethodofGeneTherapyAltersImmuneCellsforTreatmentofAdvancedMelanomaDualGeneTherapySuppressesLungCancerinPreclinicalTest59药物发现和发展OrphanDrugs:Anorphan drugisapharmaceuticalagentthathasbeendevelopedspecificallytotreatararemedicalcondition,theconditionitselfbeingreferredtoasanorphandisease.NationalOrganizationforRareDisordersEuropeanOrganizationforRareDiseases60药物发现和发展Advantages:Taxincentives.Enhancedpatentprotectionandmarketingrights.Clinicalresearchfinancialsubsidization.Riseinresearchanddevelopmen.CrownCorporation.61药物发现和发展OrphanDrugsAct:4thJanuary19836000OrphanDiseasesUnprofitableDrugDevelopmentAffecting2,00,000PersonsOrphanDrugStatusto1,090Drugs1985Amendment-MarketingExclusivityTouretteSyndromeAnOrphanDisease62药物发现和发展FDAOrphanDrugApprovals:63药物发现和发展RareDiseases&OrphanDrugs:Sr.DiseaseCauseOrphanDrug1.GauchersDiseaseGlucocerbrosidaseEnzymeMiglustat2.FabrysDiseaseGalactosidaseEnymeGalsidase3.MucopolysaccharidosisLysosomalEnzymeLaronidase4.TourettesSyndromeMotorTicsLamotrizine5.CrohnsSyndromeUnknownInfliximab6.WilsonDiseaseCopperDepositionTrientine7.SCIDAdenosineDeaminaseEnzymePegadimase64药物发现和发展65药物发现和发展