【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。WaterSolubilityasaparameterforleadoptimizationIstherearelationshipbetweenbioavailabilityandwatersolub

ility?Yes,thereis.It'scalledMAD!maximumabsorbabledose资料仅供参考,不当之处，请联系改正。Theconceptofthemaximumabsorbabledose(MAD):MAD=SxKaxSIWVxSITTSwate

rsolubilityatpH6.5(mg/ml)Katransintestinalabsorptionrateconstant(1/min)SIWVsmallintestinalwatervolume(~250ml)SITTsmallintestinalt

ransittime(~270min)WaterSolubilityasaparameterforleadoptimizationRangestypicalfordrugcandidates:Ka=0.001-0

.05min-1(50-fold)S=0.0001-100mg/ml(106-fold)Typicaldoseforadrugis1mg/kgfora70kgpatient,70mgdrugsubstancemustbeavail

ableintheblood资料仅供参考,不当之处，请联系改正。Ka(1/min)Solubility(mg/ml)MAD(mg)0.0030.0010.20.0030.012.030.0030.120.30.0031.02030.030.0012.030.030.

0120.30.030.12030.0312030WaterSolubilityasaparameterforleadoptimizationTheconceptofthemaximumabsorbabledose(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)0.1770.0030.0350.0300.0041.07070

0.0030.3460.0300.035107007000.0033.4600.0300.350WaterSolubilityasaparameterforleadoptimizationS=MAD/(KaxSIWVxSITT)资料仅供参考,不当之处，请联系改正。AzithromycinWa

terSolubilityasaparameterforleadoptimizationVerypoorabsorption(Ka=0.001min-1)Veryhighwatersolubility(S=50mg

/ml)MAD=3375mgGoodoralbioavailability!▪GoalsandConceptsinLeadOptimization•Increasingin-vitropotency/efficacyby•bioisostericreplacemen

toffunctionalgroups•gradualmodificationof3Dshapeand/orphysicochemicalproperties•ImprovingPC/ADME/Toxbehaviourb

y•replacementoftoxophores•modificationofphysicochemicalproperties(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。NOHOHOHOOCHalNOHOHOHOOCCH3NOHOHOHOOCNH2NOHOH

OBrBrHOOC➢ModificationsofaromaticsubstituentsLeadOptimization资料仅供参考,不当之处，请联系改正。NOHOHOHOOCNHOHOHOHOOCNH

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

OHOOCLeadOptimization➢Modificationsofcyclohexylgroup资料仅供参考,不当之处，请联系改正。NOHOHOHOOCNOHOHONH2NOHOHONNNHNNOHOHOOOLeadOptimization➢Modificati

onsofcarboxylgroup资料仅供参考,不当之处，请联系改正。NOHOHOHOOCNOHOOCOHOHNOHOOCOHOHLeadOptimization➢Modificationsofchainlength资料仅供参考,不当之处，请联系改正。NOHOHOHOO

CNOOOHOOCNHalOHOOCNOHOOCNHNLeadOptimization➢Modificationsofaromaticsubstituents资料仅供参考,不当之处，请联系改正。TheToplissTreeAsystematicleadoptimizati

onapproach资料仅供参考,不当之处，请联系改正。ONH2OHIIICOOHThyroxinONH2OHCH3CH3COOHCH3CH33,5-dimethyl-3'-isopropyl-thyro

nineLeadOptimization-ExampleI•hormoneofthethyroidalgland•agonistofthyroxinereceptor•bioisostericalreplacementsofiodogroups•potentagonist

ofthyroxinereceptor资料仅供参考,不当之处，请联系改正。NH2OHOHDopamineNHOHOHOHCH3AdrenalineNH2CH3Amphetamine("Speed")NHOOCH3CH3MDMA("Ecstasy")LeadOptimization-E

xampleII•hydrophilicneurotransmitters•orallyinactive•nopenetrationofblood-brainbarrier•lipophilicadrenalinemimics•orallyactive•goodpenetration

ofblood-brainbarrier•centrallystimulatingeffect资料仅供参考,不当之处，请联系改正。OOCOOHAcetylsalicylicacidNHOCOOHAmidederivative•ana

lgesicdrug•activityduetoCOXinhibition•noanalgesiceffect•bioisostericreplacementofesterbyamidefailed!LeadOptimization-ExampleIII资料仅供参考

,不当之处，请联系改正。Acetylsalicylicacid:MechanismofActionacetylgroupistransferredtoserineinactivesiteofCOX=>labileestergroupisrequired!资料仅供参考,不

当之处，请联系改正。LeadOptimization-ExampleIVFromPeptidestoPeptidomimeticsFibrinogenbindstoFibrinogenreceptor=>Initiatio

nofbloodclottingBindingisinhibitedbyArg-Gly-Asp(RGD)-tripeptid资料仅供参考,不当之处，请联系改正。LeadOptimization-ExampleIVFromPeptides

toPeptidomimeticsONHNH2NHH3NONHONHOOOArg-Gly-Asp(RGD)OONHNNNNOHNHONHOOOcyclo-(Arg-Gly-Asp-Phe-d-Val)NHNNNNOCH3NHONHOOOSOSNHNHNCOOHNH2NHOO▪TheProdrug

concept•Prodrugsareweakorinactiveprecursersofdrugs•Activedrugisonlygeneratedafterbiotransformationofprodrug•bymetaboli

ctransformation•byspontaneouschemicaldegradation•Goal:improvedADME/Tox-orphysicochemicalproperties资料仅供参考,不当之处，请联系改正。TheProdrugconcept-E

xampleIOOHOHNCH3MorphineDrug:OOONCH3CH3OCH3ODiacetyl-morphine(Heroin)Prodrug:•centralanalgesic•orallyinac

tive•slowpenetrationofblood-brainbarrier•orallyinactive•rapidpenetrationofblood-brainbarrier•degradationtomorphineinbrain•accumulationofmor

phineinbrain资料仅供参考,不当之处，请联系改正。NHNOOOCH3OOEnalapril-diesterTheProdrugconcept-ExampleIINHNOOHOCH3OHOEnalaprilatDrug:NHNOOOCH3OH

OEnalaprilProdrug:•anti-hypertensivedrug•orallyinactive•orallyactiveduetoaminoacidcarrier•degradationtoEnalaprilatbyesterasesNOOCH3NOODiketopiperazi

nderivative资料仅供参考,不当之处，请联系改正。TheProdrugconcept-ExampleIIINH2OHOHDopamineDrug:NH2OHOHCOOHL-DopaProdrug:•MorbusParkinsondrug•orallyinact

ive•slowpenetrationofblood-brainbarrier•orallyactive•rapidpenetrationofblood-brainbarrierduetoaminoacidcarrier!Auxillarydrugs:NCH3C

H3CHSelegilin•centralMAOinhibitor•preventsdopamineoxidationNNHOHOHOHOHNH2OBenserazid•peripheraldecarboxylaseinhib.•prevents

L-Dopadecarboxylation资料仅供参考,不当之处，请联系改正。NH2OHOGABA(gamma-aminobutyricacid)Drug:NClFNH2OOHProgabidProdrug:•anti-convulsiveneurotransmitter•orally

inactive•nopenetrationofblood-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.20

01,41,1308-1315)Drugscomparedtoleads➢areheavier➢aremorelipophilic➢havemoreringsystems,rotatablebonds,H-acceptors资料仅供参考,不当之处，请联系改正。TechnologyTh

eGraffinityApproachSmallmoleculesareimmobilizedongoldsurfaceProtein-LigandAffinityismeasureviaSurface-PlasmonResonance资料仅供参考,不当之处，请

联系改正。100200300400500600Molweight1,000,000100,00010,0001,00010010HTSofcompanypoolsLibrarySizedruglikeleadlikeTheGraffinityApproach:ScreeningScenari

osSARbyNMRCrystalLEADIn-SilicoScreensGraffinity资料仅供参考,不当之处，请联系改正。▪DiversityinMicrotiterplatesTechnology▪LC/MSQualitycontrol▪DaughterMicroa

rraysTheGraffinityApproach:LibrarySynthesis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▪MinimalAmountsofProtein▪Protein-LigandAffinityMaps▪Surface-PlasmonResonance▪NoAssayDevelopment▪Functi

on-BlindTheGraffinityApproach:Detection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-OrderofAffinitiesTheGraffinityApproach:Detect

ion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。