Discovery of a potent, highly selective, and orally efficacious small-molecule activator of the insulin receptor

被引：82

作者：

Liu, K ^{[1
]}

Xu, LB ^{[1
]}

Szalkowski, D ^{[1
]}

Li, ZH ^{[1
]}

Ding, V ^{[1
]}

Kwei, G ^{[1
]}

Huskey, S ^{[1
]}

Moller, DE ^{[1
]}

Heck, JV ^{[1
]}

Zhang, BB ^{[1
]}

Jones, AB ^{[1
]}

机构：

[1] Merck Res Labs, Rahway, NJ 07065 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2000年 / 43卷 / 19期

关键词：

D O I：

10.1021/jm000285q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 3,6-diaryl-2,5-dihydroxybenzoquinones were synthesized and evaluated for their abilities to selectively activate human insulin receptor tyrosine kinase (IRTK). 2,5-Dihydroxy-6-(1-methylindol-3-yl)-3-phenyl-1,4-benzoquinone (2h) was identified as a potent, highly selective, and orally active small-molecule insulin receptor activator. It activated IRTK with an EC50 of 300 nM and did not induce the activation of closely related receptors (IGFIR, EGFR, and PDGFR) at concentrations up to 30 000 nM. Oral administration of the compound to hyperglycemic db/db mice (0.1-10 mg/kg/day) elicited substantial to nearly complete correction of hyperglycemia in a dose-dependent manner. In ob/ob mice, the compound (10 mg/kg) caused significant reduction in hyperinsulinemia. A structurally related compound 2c, inactive in IRTK assay, failed to affect blood glucose level in db/db mice at equivalent exposure levels. Results from additional studies with compound 2h, aimed at evaluating classical quinone-related phenomena, provided sufficient grounds for optimism to allow more extensive toxicologic evaluation.

引用

页码：3487 / 3494

页数：8

共 43 条

[1] THE SYNTHESIS OF BRL-49653 - A NOVEL AND POTENT ANTIHYPERGLYCEMIC AGENT [J].