AMIDE AND ALPHA-KETO CARBONYL INHIBITORS OF THROMBIN BASED ON ARGININE AND LYSINE - SYNTHESIS, STABILITY AND BIOLOGICAL CHARACTERIZATION

被引:35
作者
BRADY, SF
SISKO, JT
STAUFFER, KJ
COLTON, CD
QIU, H
LEWIS, SD
NG, AS
SHAFER, JA
BOGUSKY, MJ
VEBER, DF
NUTT, RF
机构
[1] MERCK RES LABS, DEPT MED CHEM, West Point, PA 19486 USA
[2] MERCK RES LABS, DEPT BIOL CHEM, West Point, PA 19486 USA
关键词
D O I
10.1016/0968-0896(95)00105-P
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We report structure-activity investigations in a series of tripeptide amide inhibitors of thrombin, and the development of a series of highly potent active site directed ol-keto carbonyl inhibitors having the side chain of lysine at P-1. Compounds of this class are unstable by virtue of reactivity at the electrophilic carbonyl and racemization at the adjacent carbon (CH). Modifications of prototype alpha-keto-ester 8a have afforded analogs retaining nanomolar K-i. Optimal potency and stability have been realized in alpha-keto-amides 11b (K-i = 2.8 nM) and 11c (K-i = 0.25 nM).
引用
收藏
页码:1063 / 1078
页数:16
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