Design of a potent, soluble glucokinase activator with excellent in vivo efficacy

被引：84

作者：

McKerrecher, D ^{[1
]}

Allen, JV ^{[1
]}

Caulkett, PWR ^{[1
]}

Donald, CS ^{[1
]}

Fenwick, ML ^{[1
]}

Grange, E ^{[1
]}

Johnson, KM ^{[1
]}

Johnstone, C ^{[1
]}

Jones, CD ^{[1
]}

Pike, KG ^{[1
]}

Rayner, JW ^{[1
]}

Walker, RP ^{[1
]}

机构：

[1] AstraZeneca R&D Mereside, Cardiovasc & Gastrointestinal Res Area, Macclesfield SK10 4TG, Cheshire, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 10期

关键词：

diabetes; glucokinase; kinase activator; unbound clearance; GKA50;

D O I：

10.1016/j.bmcl.2006.02.022

中图分类号：

R914 [药物化学];

学科分类号：

100701 [药物化学];

摘要：

The optimisation of a series of glucokinase activators is described, including attempts to uncouple the relationship between potency and plasma protein binding, and to better understand the key pharmacokinetic properties of the series. The use of unbound clearance as an optimisation parameter facilitated the identification of GKA50, a compound which combines excellent potency and pharmacokinetics with good free drug levels and solubility, and exhibits in vivo efficacy at 1 mg/kg po in an acute rat OGTT model. (C) 2006 Elsevier Ltd. All rights reserved.

引用

页码：2705 / 2709

页数：5

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