新型肽基磷衍生物作为人钙蛋白酶I的抑制剂

Novel peptidyl phosphorus derivatives as inhibitors of human calpain I.

作者信息

Tao M, Bihovsky R, Wells G J, Mallamo J P

机构信息

Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380-4245, USA.

出版信息

J Med Chem. 1998 Sep 24;41(20):3912-6. doi: 10.1021/jm980325e.

DOI:10.1021/jm980325e

PMID:9748367

Abstract

Dipeptidyl phosphorus compounds were synthesized as potential bioisosteric mimics of peptide alpha-ketoesters and alpha-ketoacids. alpha-Ketophosphonate Cbz-Leu-Leu-P(O)(OCH3)2 (1b), containing an alpha-ketoester bioisostere, inhibits human calpain I with an IC50 = 0.43 microM. The potency of 1b compares very favorably with that of alpha-ketoester Cbz-Leu-Leu-CO2Et (IC50 = 0.60 microM). Monomethyl ketophosphonate Cbz-Leu-Leu-P(O)(OH)(OCH3) (1a, IC50 = 5.2 microM), an alpha-ketoacid mimic, is less potent. Dibutyl and dibenzyl alpha-ketophosphonates 1c,e,f are much less potent calpain inhibitors than dimethyl alpha-ketophosphonate 1b. alpha-Ketophosphinate 1g (IC50 = 0.37 microM) and alpha-ketophosphine oxide 1h (IC50 = 0.35 microM) are also potent calpain inhibitors.

摘要

二肽基磷化合物被合成为肽α-酮酯和α-酮酸的潜在生物电子等排体模拟物。含有α-酮酯生物电子等排体的α-酮膦酸酯Cbz-Leu-Leu-P(O)(OCH3)2（1b）对人钙蛋白酶I具有抑制作用，IC50 = 0.43微摩尔。1b的效力与α-酮酯Cbz-Leu-Leu-CO2Et（IC50 = 0.60微摩尔）相比非常有利。作为α-酮酸模拟物的单甲基酮膦酸酯Cbz-Leu-Leu-P(O)(OH)(OCH3)（1a，IC50 = 5.2微摩尔）效力较低。二丁基和二苄基α-酮膦酸酯1c、e、f作为钙蛋白酶抑制剂的效力远低于二甲基α-酮膦酸酯1b。α-酮次膦酸酯1g（IC50 = 0.37微摩尔）和α-酮氧化膦1h（IC50 = 0.35微摩尔）也是有效的钙蛋白酶抑制剂。