Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: Design, synthesis, and preclinical characterization

被引：137

作者：

Elokdah, H

Abou-Gharbia, M

Hennan, JK

McFarlane, G

Mugford, CP

Krishnamurthy, G

Crandall, DL

机构：

[1] Wyeth Ayerst Res, Chem & Screening Sci, Princeton, NJ 08543 USA

[2] Wyeth Ayerst Res, Cardiovasc Metab Dis, Collegeville, PA 19426 USA

[3] Wyeth Ayerst Res, Drug Safety & Metab, Collegeville, PA 19426 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 14期

关键词：

D O I：

10.1021/jm049766q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Indole oxoacetic acid derivatives were prepared and evaluated for in vitro binding to and inactivation of human plasminogen activator inhibitor-1 (PAI-1). SAR based on biochemical, physiological, and pharmacokinetic attributes led to identification of tiplaxtinin as the optimal selective PAI-1 inhibitor. Tiplaxtinin exhibited in vivo oral efficacy in two different models of acute arterial thrombosis. The remarkable preclinical safety and metabolic stability profiles of tiplaxtinin led to advancing the compound to clinical trials.

引用

页码：3491 / 3494

页数：4

共 21 条

[1] Antithrombotic activity of a monoclonal antibody inducing the substrate form of plasminogen activator inhibitor type 1 in rat models of venous and arterial thrombosis [J].