Development of potent non-carbohydrate imidazole-based small molecule selectin inhibitors with antiinflammatory activity

被引：65

作者：

Slee, DH ^{[1
]}

Romano, SJ ^{[1
]}

Yu, JH ^{[1
]}

Nguyen, TN ^{[1
]}

John, JK ^{[1
]}

Raheja, NK ^{[1
]}

Axe, FU ^{[1
]}

Jones, TK ^{[1
]}

Ripka, WC ^{[1
]}

机构：

[1] Ontogen Corp, Carlsbad, CA USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2001年 / 44卷 / 13期

关键词：

D O I：

10.1021/jm000508c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of non-carbohydrate imidazole-based selectin inhibitors has been discovered via high-throughput screening using a P-selectin ELISA-based assay system. The initial lead 1 had an IC(50) of 17 muM in the P-selectin ELISA; this potency was significantly improved via an extensive SAR exploration. One of the current lead compounds (29) has an IC(50) of 300 nM in a P-selectin ELISA; it also has good activity in P- and E-selectin cell adhesion assays and shows efficacy in vivo. These compounds represent a novel series of sLe(X) mimetics with antiinflammatory activity. Their unique profile supports our interest in their further evaluation as drug candidates for the treatment of inflammation. Herein we describe the syntheses, optimization, and SAR of this series of novel potent selectin antagonists.

引用

页码：2094 / 2107

页数：14

共 78 条

[1] ADHESION MOLECULES AND INFLAMMATORY INJURY [J].