福辛普利赖诺普利.pptVIP

1ACEInhibitorDesign1.通过抑制ACE抑制Ang?生成降低血压2研究Angl如何与受体结合来设计新药的结构ACEI有多种上市，按化学结构分为三类：1含-SH；2含二COOH；3含PO21卡托普利2苯丁酸脯氨酸苯丁酯脯氨酸酯（依那普利）3福辛普利赖诺普利贝那普利典型ACEI结构式AngiotensinIandACEReceptorFitH2N-Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7ACEAngiotensinI(naturalsubstrateforACE)Phe8His9Leu10“Hydrolyticsite”“H-bondingsite”“Cationicsite”受体仅与三个氨基酸结合，左边7个氨基酸不重要，设计药物结构，仅与此三个有关。SAR(structure-activityrelationships)forACEInhibitorsACE“Hydrolyticsite”“H-bondingsite”“Cationicsite”(1)aZn+2bindinggroupasulfhydrylgroup(-SH)acarboxylicacid(-COOH)(anesterastheprodrug)aphosphinicacid(2)aH-bindinggroupanamide(3)acarboxylicacidgroupacarboxylate(-COO-)(4)aphenylalkylgroupneartheZn+2bindingACEInhibitorDesignbyReceptorFitACE“Hydrolyticsite”“H-bondingsite”“Cationicsite”Enalapril(anesterprodrug)ACEIC50=1.2mgmimicofPhe8ofAngiotensinIEnalaprilat(anacid;activeform)依那普利拉ACEIC50=0.0012mghepaticesterasepoororalabsorption(2carboxylates+1amine)依那普利比卡托普利强10倍苯酯脯氨酸将巯基换成羧基并成酯后，称为Enalapril是前药，该药可改善口服吸收。能进入中枢。是一个长效药。ACEInhibitorDesignbyReceptorFitACE“Hydrolyticsite”“H-bondingsite”“Cationicsite”Lisinopril(theLysanalogofenalapril)notanesterprodrug(poorabsorption(30%))“lysine”赖诺普利赖氨酸结构特殊，含有碱性残基（CH2)4NH2;2COOH未被酯化；但吸收好，与卡托普利拉是唯一使用的两个非前体药物。ACEInhibitorDesignbyReceptorFitACE“Hydrolyticsite”“H-bondingsite”“Cationicsite”Benazepril(anesterprodrug)Benazeprilat(anacid;activeform)hepaticesteraseBenzozepineringinsteadoftheprolinegroup贝那普利贝那普利酸羧基酯化，脂溶性增加，利于吸收，不良反应降低，作用增强。ACEInhibitorDesignbyReceptorFitFosinopril(anesterprodrug)Fosinoprilat(anphosphinicacid;activeform)bindstoZn+2Potency:CaptoprilFosinoprilEnalaprilH-O-Hhepaticesterase福辛普利含磷酰结构以磷