Disubstituted indazoles as potent antagonists of the integrin αvβ3

被引：78

作者：

Batt, DG ^{[1
]}

Petraitis, JJ ^{[1
]}

Houghton, GC ^{[1
]}

Modi, DP ^{[1
]}

Cain, GA ^{[1
]}

Corjay, MH ^{[1
]}

Mousa, SA ^{[1
]}

Bouchard, PJ ^{[1
]}

Forsythe, MS ^{[1
]}

Harlow, PP ^{[1
]}

Barbera, FA ^{[1
]}

Spitz, SM ^{[1
]}

Wexler, RR ^{[1
]}

Jadhav, PK ^{[1
]}

机构：

[1] DuPont Pharmaceut Co, Wilmington, DE 19880 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2000年 / 43卷 / 01期

关键词：

D O I：

10.1021/jm990049j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new series of indazole-containing alpha(v)beta(3) integrin antagonists is described. Starting with lead compound 18a, variations in a number of structural features were explored with respect to inhibition of the binding of beta(3)-transfected 293 cells to fibrinogen and to selectivity for alpha(v)beta(3) over GPIIbIIIa, another RGD-binding integrin. Indazoles attached to a 2-aminopyridine or 2-aminoimidazole by a propylene linker at the indazole 1-position and to a diaminopropionate derivative via a 5-carboxylate amide provided the best potency with moderate selectivity. Several differences in the SAR of the diaminopropionate moiety were observed between this series and a series of isoxazoline-based selective GPIIbIIIa antagonists. Compound 34a (SM256) was a potent antagonist of alpha(v)beta(3) (IC50 2.3 nM) with 9-fold selectivity over GPIIbIIIa.

引用

页码：41 / 58

页数：18

共 48 条

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