2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[H]quinoline-4-carboxylic acid (PSI-697):: Identification of a clinical candidate from the quinoline salicylic acid series of P-selectin antagonists

被引：72

作者：

Kaila, Neelu ^{[1
]}

Janz, Kristin ^{[1
]}

Huang, Adrian ^{[1
]}

Moretto, Alessandro ^{[1
]}

DeBernardo, Silvano ^{[1
]}

Bedard, Patricia W. ^{[1
]}

Tam, Steve ^{[1
]}

Clerin, Valerie ^{[1
]}

Keith, James C., Jr. ^{[1
]}

Tsao, Desiree H. H. ^{[1
]}

Sushkova, Natalia ^{[1
]}

Shaw, Gray D. ^{[1
]}

Camphausen, Raymond T. ^{[1
]}

Schaub, Robert G. ^{[1
]}

Wang, Qin ^{[1
]}

机构：

[1] Wyeth Res, Chem & Screening Sci, Cardiovasc & Metab Dis, Drug Safety & Metab, Cambridge, MA 02140 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 01期

关键词：

D O I：

10.1021/jm060631p

中图分类号：

R914 [药物化学];

学科分类号：

100701 [药物化学];

摘要：

P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which subsequently leads to firm adherence and leukocyte transmigration through the vessel wall into the surrounding tissues. P-selectin is upregulated on the surface of both platelets and endothelium in a variety of atherosclerosis-associated conditions. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of atherosclerosis. High-throughput screening and subsequent analoging had led to the identification of compound 1 as the lead candidate. Herein, we report the continuation of this work and the discovery of a second-generation series, the tetrahydrobenzoquinoline salicylic acids. These compounds have improved pharmacokinetic properties, and a number of them have shown oral efficacy in mouse and rat models of atherogenesis and vascular injury. The lead 31 (PSI-697), is currently in clinical development for the treatment of atherothrombotic vascular events.

引用

页码：40 / 64

页数：25

共 67 条

[1]

Selectin blockade prevents antigen-induced late bronchial responses and airway hyperresponsiveness in allergic sheep [J].