人中性粒细胞弹性蛋白酶的抑制作用。3. 一种口服活性烯醇乙酸酯前药。

Inhibition of human neutrophil elastase. 3. An orally active enol acetate prodrug.

作者信息

Burkhart J P, Koehl J R, Mehdi S, Durham S L, Janusz M J, Huber E W, Angelastro M R, Sunder S, Metz W A, Shum P W

机构信息

Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215.

出版信息

J Med Chem. 1995 Jan 20;38(2):223-33. doi: 10.1021/jm00002a003.

DOI:10.1021/jm00002a003

PMID:7830264

Abstract

Several analogs of N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N-[3,3,4,4,4-penta fluoro-1- (1-methylethyl)-2-oxobutyl]-L-prolinamide (1), in which the chiral center of the P1 residue has been eliminated, were synthesized and tested as inhibitors of human neutrophil elastase (HNE). Observations made during the course of this work led to the development of a single-step, stereoselective synthesis of E-enol acetate derivatives from HNE inhibitors containing a mixture of epimers at P1. In vitro studies, in the presence of added esterase, and 19F NMR studies, in biological media, indicated that the E-enol acetate derivatives should act as prodrugs in vivo. The ED50 value for (E)-N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N-[2- (acetyloxy)-3,3,4,4,4-pentafluoro-1-(1-methylethyl)-1-buteny l]-L-prolinamide (20), when administered orally in the hamster lung hemorrhage model, was 9 mg/kg.

摘要

合成了几种N-[4-(4-吗啉基羰基)苯甲酰基]-L-缬氨酰-N-[3,3,4,4,4-五氟-1-(1-甲基乙基)-2-氧代丁基]-L-脯氨酰胺(1)的类似物，其中P1残基的手性中心已被消除，并作为人中性粒细胞弹性蛋白酶(HNE)的抑制剂进行了测试。在这项工作过程中所做的观察导致了从在P1处含有差向异构体混合物的HNE抑制剂一步立体选择性合成E-烯醇乙酸酯衍生物。在添加酯酶的情况下进行的体外研究以及在生物介质中进行的19F NMR研究表明，E-烯醇乙酸酯衍生物在体内应作为前药起作用。当在仓鼠肺出血模型中口服给药时，(E)-N-[4-(4-吗啉基羰基)苯甲酰基]-L-缬氨酰-N-[2-(乙酰氧基)-3,3,4,4,4-五氟-1-(1-甲基乙基)-1-丁烯基]-L-脯氨酰胺(20)的ED50值为9 mg/kg。