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1、血腦屏障Blood-BrainBarrierBlood-BrainBarrierintroduction2WhatistheBloodBrainBarrier3Braindistributionmechanismsmechanismslimittheaccessofcompoundstobraincellsbyaffectingthedistributionofcompoundtoorwithinthebrain7Metabolicclearance8Plasmaproteinbinding9Bounddrugcanreleaseinbrainmicrovesselcirculation1
2、0Nonspecificbindingtoproteinsandlipidsinbraintissue11Summarizethemajormechanismsaffectingbrainexposure12Brain–CSFBarrier13InterpretingDataforBrainPenetrationThemostcommonlyusedbrainpenetrationdataisB/P;itslogisLogBB.B/Pisiscalculatedfromvariousdata:B/P>0.3isusedasaminimumguidelineforCNSdiscoverypr
3、ojects.yetsomecommercialCNSdrugshaveB/P<0.1.14ThelimitationofB/P15Papp,PS,andt1/2eq.inIndicatetheRateofBBBPermeability16EffectsofBrainPenetrationBBBpenetrationisnecessaryforCNSdrugs.10However,drugsfortherapyinperipheraltissuesmaycausesideeffectsinthebrain;therefore,itisdesirablethattheyhaveminimal
4、penetrationintothebrain.ItmaybepossibletoreduceCNSsideeffectsofperipheraldrugsbymakingstructuralmodificationsthatreducethebrainpenetration.17Structure–BBBPenetrationRelationshipskeystructuralpropertiesfordiscoveryofCNSdrugsAsetofphysicochemicalBBBruleswasfirstproposedbyPardridgeAnothersetofBBBrule
5、swascompiledbyClarkandLobell18StructureModificationStrategiestoImproveBrainPenetration19ReducehydrogenbondstoimproveBBBpermeation20IncreaseLipophilicitytoimproveBBBpermeationItshouldbenotedthatincreasinglipophilicitytoimproveBBBpermeationalsocanhaveanegativeeffectonBBBpenetration.Accordingtothe“ph
6、armacokineticrule,”increasinglipophilicityalsoincreasesnonspecificbindinginthebrain,reducesfreecompoundconcentrationinECFatbraincells,decreasessolubilityandactivity.Therefore,itisimportanttobalancelipophilicityforoptimizingpermeabilityandminimizingbrainbinding.21increasingLipophilicitytoomuchresul
7、tsinnegativeeffect22ReplaceCarboxylicAcidGroupstoimprovebrainpenetration23decreasepKatoimprovebrainpenetration24Addintramolecularhydrogenbondtoincreasebrainpenetration25Increasemetabolicstabilitytoimprovebrainpen
