蛋白质法尼基转移酶的强效且选择性含非半胱氨酸抑制剂。

Potent and selective non-cysteine-containing inhibitors of protein farnesyltransferase.

作者信息

Augeri D J, O'Connor S J, Janowick D, Szczepankiewicz B, Sullivan G, Larsen J, Kalvin D, Cohen J, Devine E, Zhang H, Cherian S, Saeed B, Ng S C, Rosenberg S

机构信息

Departments of Cancer Research, D-47B, and Combinatorial Chemistry, D-4CP, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.

出版信息

J Med Chem. 1998 Oct 22;41(22):4288-300. doi: 10.1021/jm980298s.

DOI:10.1021/jm980298s

PMID:9784104

Abstract

Potent and selective non-thiol-containing inhibitors of protein farnesyltransferase are described. FTI-276 (1) was transformed into pyridyl ether analogue 19. The potency of pyridyl ether 19 was improved by modification of the biphenyl core to that of an o-tolyl substituted biphenyl core to give 29. In addition to 0.4 nM in vitro potency, 29 displayed 350 nM potency in whole cells as the parent carboxylic acid. The o-tolyl biphenyl core dramatically and unexpectedly enhanced the potency of other compounds as exemplified by 46, 47, 48, and 49.

摘要

本文描述了强效且具有选择性的不含硫醇的蛋白质法尼基转移酶抑制剂。FTI-276（1）被转化为吡啶基醚类似物19。通过将联苯核心修饰为邻甲苯基取代的联苯核心得到29，从而提高了吡啶基醚19的效力。除了在体外具有0.4 nM的效力外，29作为母体羧酸在全细胞中显示出350 nM的效力。邻甲苯基联苯核心显著且意外地提高了其他化合物的效力，如46、47、48和49所示。