Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits

被引：316

作者：

MacPherson, LJ

Bayburt, EK

Capparelli, MP

Carroll, BJ

Goldstein, R

Justice, MR

Zhu, LJ

Hu, SI

Melton, RA

Fryer, L

Goldberg, RL

Doughty, JR

Spirito, S

Blancuzzi, V

Wilson, D

OByrne, EM

Ganu, V

Parker, DT

机构：

[1] Research Department, Novartis Pharmaceuticals, Summit, NJ 07901

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1997年 / 40卷 / 16期

关键词：

D O I：

10.1021/jm960871c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure-activity relationships of a lead hydroxamic acid inhibitor of recombinant human stromelysin were systematically defined by taking advantage of a concise synthesis that allowed diverse functionality to be explored at each position in a template. An ex vivo rat model and an in vivo rabbit model of stromelysin-induced cartilage degradation were used to further optimize these analogs for oral activity and duration of action. The culmination of these modifications resulted in CGS 27023A, a potent, orally active stromelysin inhibitor that blocks the erosion of cartilage matrix.

引用

页码：2525 / 2532

页数：8

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