【文档说明】药物优化医学宣教课件.ppt，共(38)页，2.870 MB，由小橙橙上传

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资料仅供参考,不当之处，请联系改正。Whydodrugsfailinclinicaldevelopment?(TakenfromKennedy,DrugDiscoveryToday,2(10),1997,436-

444)资料仅供参考,不当之处，请联系改正。WaterSolubilityasaparameterforleadoptimizationIstherearelationshipbetweenbioavailabilityandwatersolubility?Yes,th

ereis.It'scalledMAD!maximumabsorbabledose资料仅供参考,不当之处，请联系改正。Theconceptofthemaximumabsorbabledose(MAD):MAD=SxKaxSIWVxSITTSwatersolubilityatpH6.5(mg

/ml)Katransintestinalabsorptionrateconstant(1/min)SIWVsmallintestinalwatervolume(~250ml)SITTsmallintestinaltransittime(~270min)WaterSolubilityasapa

rameterforleadoptimizationRangestypicalfordrugcandidates:Ka=0.001-0.05min-1(50-fold)S=0.0001-100mg/ml(106-fold)Typicald

oseforadrugis1mg/kgfora70kgpatient,70mgdrugsubstancemustbeavailableintheblood资料仅供参考,不当之处，请联系改正。Ka(1/min)Solubility(mg/ml)MAD(mg)0.0030.0010.20.003

0.012.030.0030.120.30.0031.02030.030.0012.030.030.0120.30.030.12030.0312030WaterSolubilityasaparameterforleadoptimizati

onTheconceptofthemaximumabsorbabledose(MAD):资料仅供参考,不当之处，请联系改正。Howsolubledoesadrugcandidatehavetobe???Dose(mg/kg)Dose(mg)MAD(mg)Ka(1/min)

Solubility(mg/ml)0.1770.0030.0350.0300.0041.070700.0030.3460.0300.035107007000.0033.4600.0300.350WaterSolubilityasaparameterforleadoptimizatio

nS=MAD/(KaxSIWVxSITT)资料仅供参考,不当之处，请联系改正。AzithromycinWaterSolubilityasaparameterforleadoptimizationVerypoora

bsorption(Ka=0.001min-1)Veryhighwatersolubility(S=50mg/ml)MAD=3375mgGoodoralbioavailability!▪Goalsa

ndConceptsinLeadOptimization•Increasingin-vitropotency/efficacyby•bioisostericreplacementoffunctionalgroups

•gradualmodificationof3Dshapeand/orphysicochemicalproperties•ImprovingPC/ADME/Toxbehaviourby•replacementoftoxophores•modificationofphysicochem

icalproperties(e.g.lipophilicity,charge,flexibilityetc.)•replacementofmetabolicallylabilegroups•pro-drugconcept资料仅供参考,不当之处

，请联系改正。NOHOHOHOOCLeadOptimizationWhatcanbemodified?资料仅供参考,不当之处，请联系改正。NOHOHOHOOCHalNOHOHOHOOCCH3NOHOHOHOOCNH2NOHOHOBrBrHOOC➢Modificationsofaromat

icsubstituentsLeadOptimization资料仅供参考,不当之处，请联系改正。NOHOHOHOOCNHOHOHOHOOCNHOHOHOHOOCNOHOHHOOCLeadOptimization➢Modificationsofamidegroup资料仅供参考,不当

之处，请联系改正。NOHOHOHOOCNOHOHOHOOCNNOHOHOHOOCNONOHOHHOOCNOHOHOHOOCLeadOptimization➢Modificationsofcyclohexylgroup资料仅供参考,不当之处，请联系改正。NOHOHOHOOCN

OHOHONH2NOHOHONNNHNNOHOHOOOLeadOptimization➢Modificationsofcarboxylgroup资料仅供参考,不当之处，请联系改正。NOHOHOHOOCNOHOOCOHOHN

OHOOCOHOHLeadOptimization➢Modificationsofchainlength资料仅供参考,不当之处，请联系改正。NOHOHOHOOCNOOOHOOCNHalOHOOCNOHOOCNHNLeadOptimization➢Modificationsofaromaticsu

bstituents资料仅供参考,不当之处，请联系改正。TheToplissTreeAsystematicleadoptimizationapproach资料仅供参考,不当之处，请联系改正。ONH2OHIIICOOHThyroxinONH2OHCH3CH3COOHCH3CH33,5-dim

ethyl-3'-isopropyl-thyronineLeadOptimization-ExampleI•hormoneofthethyroidalgland•agonistofthyroxinereceptor•bioisostericalr

eplacementsofiodogroups•potentagonistofthyroxinereceptor资料仅供参考,不当之处，请联系改正。NH2OHOHDopamineNHOHOHOHCH3AdrenalineNH2CH3Amphetamine("Sp

eed")NHOOCH3CH3MDMA("Ecstasy")LeadOptimization-ExampleII•hydrophilicneurotransmitters•orallyinactive•nopenetrationofbloo

d-brainbarrier•lipophilicadrenalinemimics•orallyactive•goodpenetrationofblood-brainbarrier•centrallystimulatingeffect资料仅供参考,不当之处，请联

系改正。OOCOOHAcetylsalicylicacidNHOCOOHAmidederivative•analgesicdrug•activityduetoCOXinhibition•noanalgesiceffect

•bioisostericreplacementofesterbyamidefailed!LeadOptimization-ExampleIII资料仅供参考,不当之处，请联系改正。Acetylsalicylicacid:MechanismofActionacetylgroupistransferr

edtoserineinactivesiteofCOX=>labileestergroupisrequired!资料仅供参考,不当之处，请联系改正。LeadOptimization-ExampleIVFromPeptidestoPeptidomimeticsFibrinogenbindstoF

ibrinogenreceptor=>InitiationofbloodclottingBindingisinhibitedbyArg-Gly-Asp(RGD)-tripeptid资料仅供参考,不当之处，请联系改正。LeadO

ptimization-ExampleIVFromPeptidestoPeptidomimeticsONHNH2NHH3NONHONHOOOArg-Gly-Asp(RGD)OONHNNNNOHNHONHOOOcyclo-(Arg-Gly-Asp-Phe-d-Val)NHNNNNOCH3NHONH

OOOSOSNHNHNCOOHNH2NHOO▪TheProdrugconcept•Prodrugsareweakorinactiveprecursersofdrugs•Activedrugisonlygener

atedafterbiotransformationofprodrug•bymetabolictransformation•byspontaneouschemicaldegradation•Goal:improvedADME/Tox-orphysicochemicalproperties资料仅供参

考,不当之处，请联系改正。TheProdrugconcept-ExampleIOOHOHNCH3MorphineDrug:OOONCH3CH3OCH3ODiacetyl-morphine(Heroin)Prodrug:•centralanalgesic•o

rallyinactive•slowpenetrationofblood-brainbarrier•orallyinactive•rapidpenetrationofblood-brainbarrier•degradat

iontomorphineinbrain•accumulationofmorphineinbrain资料仅供参考,不当之处，请联系改正。NHNOOOCH3OOEnalapril-diesterTheProdrugconcept-Exa

mpleIINHNOOHOCH3OHOEnalaprilatDrug:NHNOOOCH3OHOEnalaprilProdrug:•anti-hypertensivedrug•orallyinactive•orallyactivedue

toaminoacidcarrier•degradationtoEnalaprilatbyesterasesNOOCH3NOODiketopiperazinderivative资料仅供参考,不当之处，请联系改正。TheProdrugconcept-ExampleI

IINH2OHOHDopamineDrug:NH2OHOHCOOHL-DopaProdrug:•MorbusParkinsondrug•orallyinactive•slowpenetrationofblood-

brainbarrier•orallyactive•rapidpenetrationofblood-brainbarrierduetoaminoacidcarrier!Auxillarydrugs:NCH3CH3CHSelegilin•centralMAOinhibi

tor•preventsdopamineoxidationNNHOHOHOHOHNH2OBenserazid•peripheraldecarboxylaseinhib.•preventsL-Dopadecarboxylation资料仅供参考,不当之处，请联系改正。NH2

OHOGABA(gamma-aminobutyricacid)Drug:NClFNH2OOHProgabidProdrug:•anti-convulsiveneurotransmitter•orallyinactive•nopenetra

tionofblood-brainbarrier•orallyactive•rapidpenetrationofblood-brainbarrierTheProdrugconcept-ExampleIV资料仅供参考

,不当之处，请联系改正。DrugDiscovery:What'snext?资料仅供参考,不当之处，请联系改正。Differencesbetweenleadsanddrugs(TakenfromOpreaetal.,J.Chem.Inf.Comput.Sci.2001,41,1308-1315

)Drugscomparedtoleads➢areheavier➢aremorelipophilic➢havemoreringsystems,rotatablebonds,H-acceptors资料仅供参考,不当之处，请联系改正

。TechnologyTheGraffinityApproachSmallmoleculesareimmobilizedongoldsurfaceProtein-LigandAffinityismeasureviaSurface-Plas

monResonance资料仅供参考,不当之处，请联系改正。100200300400500600Molweight1,000,000100,00010,0001,00010010HTSofcompanypoolsLibrarySizedruglikele

adlikeTheGraffinityApproach:ScreeningScenariosSARbyNMRCrystalLEADIn-SilicoScreensGraffinity资料仅供参考,不当之处，请联系改正

。▪DiversityinMicrotiterplatesTechnology▪LC/MSQualitycontrol▪DaughterMicroarraysTheGraffinityApproach:LibraryS

ynthesis资料仅供参考,不当之处，请联系改正。TechnologyTheGraffinityApproach:LibrarySynthesis资料仅供参考,不当之处，请联系改正。Technology▪Min

imalAmountsofProtein▪Protein-LigandAffinityMaps▪Surface-PlasmonResonance▪NoAssayDevelopment▪Function-BlindTheGraffinityApproach:Detecti

on资料仅供参考,不当之处，请联系改正。PrincipleofSurfacePlasmonResonance-ameanstodetectProtein-Ligandbinding资料仅供参考,不当之处，请联系改正。TechnologyImmediateRank-OrderofAffin

itiesTheGraffinityApproach:Detection资料仅供参考,不当之处，请联系改正。TechnologyTheGraffinityApproach:SARAnalysis资料仅供参考,不当之处，请联系改正。我使用的“设置透明色”处理的资料

仅供参考,不当之处，请联系改正。