INHIBITION OF HUMAN NEUTROPHIL ELASTASE WITH PEPTIDYL ELECTROPHILIC KETONES .2. ORALLY-ACTIVE P-G-VAL-PRO-VAL PENTAFLUOROETHYL KETONES

被引：52

作者：

ANGELASTRO, MR ^{[1
]}

BAUGH, LE ^{[1
]}

BEY, P ^{[1
]}

BURKHART, JP ^{[1
]}

CHEN, TM ^{[1
]}

DURHAM, SL ^{[1
]}

HARE, CM ^{[1
]}

HUBER, EW ^{[1
]}

JANUSZ, MJ ^{[1
]}

KOEHL, JR ^{[1
]}

MARQUART, AL ^{[1
]}

MEHDI, S ^{[1
]}

PEET, NP ^{[1
]}

机构：

[1] MARION MERRELL DOW RES INST, CINCINNATI, OH 45215 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1994年 / 37卷 / 26期

关键词：

D O I：

10.1021/jm00052a013

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Valylprolylvalyl pentafluoroethyl ketones with different N-protecting groups were evaluated in vitro and in vivo as inhibitors of human neutrophil elastase (HNE). Several of these compounds were found to be orally active in HNE-induced rat and hamster lung hemorrhage models. The compound with 4-(4-morpholinylcarbonyl)benzoyl as the protecting group, 71 (MDL 101,146), was studied in greater detail. Hydration and epimerization studies were performed on 71 and related compounds in various media, including human blood serum. Highperformance liquid chromatography studies on a reversed-phase system as a measure of the Lipophilicity of 71. and related compounds revealed a small range of relative retention times wherein the orally active compounds fell. The K-i value determined for 71 vs HNE was 25 nM.

引用

页码：4538 / 4553

页数：16

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