A novel series of indazole-/indole-based glucagon receptor antagonists

被引：12
|
作者：
Lin, Songnian [1 ]
Zhang, Fengqi [1 ]
Jiang, Guoqiang [1 ]
Qureshi, Sajjad A. [1 ]
Yang, Xiaodong [1 ]
Chicchi, Gary G. [1 ]
Tota, Laurie [1 ]
Bansal, Alka [1 ]
Brady, Edward [1 ]
Trujillo, Maria [1 ]
Salituro, Gino [1 ]
Miller, Corey [1 ]
Tata, James R. [1 ]
Zhang, Bei B. [1 ]
Parmee, Emma R. [1 ]
机构：
[1] Merck Res Labs, Early Dev & Discovery Sci & Preclin Dev, Kenilworth, NJ 07033 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 19期
关键词：
Glucagon receptor antagonist; Indazole; Indole; Diabetes; Glucose lowering; HEPATIC GLUCOSE-PRODUCTION; THERAPEUTIC TARGET;
D O I：
10.1016/j.bmcl.2015.08.015
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A novel, potent series of glucagon receptor antagonists (GRAs) was discovered. These indazole-and indole-based compounds were designed on an earlier pyrazole-based GRA lead MK-0893. Structure-activity relationship (SAR) studies were focused on the C3 and C6 positions of the indazole core, as well as the benzylic position on the N-1 of indazole. Multiple potent GRAs were identified with excellent in vitro profiles and good pharmacokinetics in rat. Among them, GRA 16d was found to be orally active in blunting glucagon induced glucose excursion in an acute glucagon challenge model in glucagon receptor humanized (hGCGR) mice at 1, 3 and 10 mg/kg (mpk), and significantly lowered acute glucose levels in hGCGR ob/ob mice at 3 mpk dose. (C) 2015 Elsevier Ltd. All rights reserved.
引用
收藏
页码：4143 / 4147
页数：5
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