药物优化ppt课件.ppt

LeadOptimization FromLeadstoDevelopmentalCandidates Whydodrugsfailinclinicaldevelopment TakenfromKennedy DrugDiscoveryToday 2 10 1997 436 444 WaterSolubilityasaparameterforleadoptimization Istherearelationshipbetweenbioavailabilityandwatersolubility Yes thereis It scalledMAD maximumabsorbabledose Theconceptofthemaximumabsorbabledose MAD MAD SxKaxSIWVxSITTSwatersolubilityatpH6 5 mg ml Katransintestinalabsorptionrateconstant 1 min SIWVsmallintestinalwatervolume 250ml SITTsmallintestinaltransittime 270min WaterSolubilityasaparameterforleadoptimization Rangestypicalfordrugcandidates Ka 0 001 0 05min 1 50 fold S 0 0001 100mg ml 106 fold Typicaldoseforadrugis1mg kg fora70kgpatient 70mgdrugsubstancemustbeavailableintheblood WaterSolubilityasaparameterforleadoptimization Theconceptofthemaximumabsorbabledose MAD Howsolubledoesadrugcandidatehavetobe WaterSolubilityasaparameterforleadoptimization S MAD KaxSIWVxSITT Azithromycin WaterSolubilityasaparameterforleadoptimization Verypoorabsorption Ka 0 001min 1 Veryhighwatersolubility S 50mg ml MAD 3375mg Goodoralbioavailability GoalsandConceptsinLeadOptimization Increasingin vitropotency efficacybybioisostericreplacementoffunctionalgroupsgradualmodificationof3Dshapeand orphysicochemicalpropertiesImprovingPC ADME Toxbehaviourbyreplacementoftoxophoresmodificationofphysicochemicalproperties e g lipophilicity charge flexibilityetc replacementofmetabolicallylabilegroupspro drugconcept LeadOptimization Whatcanbemodified Modificationsofaromaticsubstituents LeadOptimization LeadOptimization Modificationsofamidegroup LeadOptimization Modificationsofcyclohexylgroup LeadOptimization Modificationsofcarboxylgroup LeadOptimization Modificationsofchainlength LeadOptimization Modificationsofaromaticsubstituents TheToplissTreeAsystematicleadoptimizationapproach LeadOptimization ExampleI hormoneofthethyroidalglandagonistofthyroxinereceptor bioisostericalreplacementsofiodogroupspotentagonistofthyroxinereceptor LeadOptimization ExampleII hydrophilicneurotransmittersorallyinactivenopenetrationofblood brainbarrier lipophilicadrenalinemimicsorallyactivegoodpenetrationofblood brainbarriercentrallystimulatingeffect analgesicdrugactivityduetoCOXinhibition noanalgesiceffectbioisostericreplacementofesterbyamidefailed LeadOptimization ExampleIII Acetylsalicylicacid MechanismofAction acetylgroupistransferredtoserineinactivesiteofCOX labileestergroupisrequired LeadOptimization ExampleIVFromPeptidestoPeptidomimetics LeadOptimization ExampleIVFromPeptidestoPeptidomimetics TheProdrugconcept ProdrugsareweakorinactiveprecursersofdrugsActivedrugisonlygeneratedafterbiotransformationofprodrugbymetabolictransformationbyspontaneouschemicaldegradationGoal improvedADME Tox orphysicochemicalproperties TheProdrugconcept ExampleI Drug Prodrug centralanalgesicorallyinactiveslowpenetrationofblood brainbarrier orallyinactiverapidpenetrationofblood brainbarrierdegradationtomorphineinbrainaccumulationofmorphineinbrain TheProdrugconcept ExampleII Drug Prodrug anti hypertensivedrugorallyinactive orallyactiveduetoaminoacidcarrierdegradationtoEnalaprilatbyesterases TheProdrugconcept ExampleIII Drug Prodrug MorbusParkinsondrugorallyinactiveslowpenetrationofblood brainbarrier orallyactiverapidpenetrationofblood brainbarrierduetoaminoacidcarrier Auxillarydrugs centralMAOinhibitorpreventsdopamineoxidation peripheraldecarboxylaseinhib preventsL Dopadecarboxylation Drug Prodrug anti convulsiveneurotransmitterorallyinactivenopenetrationofblood brainbarrier orallyactiverapidpenetrationofblood brainbarrier TheProdrugconcept ExampleIV DrugDiscovery What snext Differencesbetweenleadsanddrugs TakenfromOpreaetal J Chem Inf Comput Sci 2001 41 1308 1315 Drugscomparedtoleadsareheavieraremorelipophilichavemoreringsystems rotatablebonds H acceptors Technology TheGraffinityApproach SmallmoleculesareimmobilizedongoldsurfaceProtein LigandAffinityismeasuredviaSurface PlasmonResonance 100200300400500600Molweight 1 000 000100 00010 0001 00010010 LibrarySize druglike leadlike TheGraffinityApproach ScreeningScenarios DiversityinMicrotiterplates Technology LC MSQualitycontrol DaughterMicroarrays TheGraffinityApproach LibrarySynthesis Technology TheGraffinityApproach LibrarySynthesis Technology MinimalAmountsofProteinProtein LigandAffinityMapsSurface PlasmonResonanceNoAssayDevelopmentFunction Blind TheGraffinityApproach Detection Principl