Discovery of novel, potent, selective, and orally active human glucagon receptor antagonists containing a pyrazole core

被引：41

作者：

Shen, Dong-Ming ^{[1
]}

Brady, Edward J. ^{[2
]}

Candelore, Mari R. ^{[3
]}

Dallas-Yang, Qing ^{[3
]}

Ding, Victor D. -H. ^{[3
]}

Feeney, William P. ^{[4
]}

Jiang, Guoquiang ^{[3
]}

McCann, Margaret E. ^{[2
]}

Mock, Steve ^{[1
]}

Qureshi, Sajjad A. ^{[3
]}

Saperstein, Richard ^{[2
]}

Shen, Xiaolan ^{[4
]}

Tong, Xinchun ^{[1
]}

Tota, Laurie M. ^{[3
]}

Wright, Michael J. ^{[3
]}

Yang, Xiaodong ^{[3
]}

Zheng, Song ^{[1
]}

Chapman, Kevin T. ^{[1
]}

Zhang, Bei B. ^{[3
]}

Tata, James R. ^{[1
]}

Parmee, Emma R. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Basic Chem, Rahway, NJ 07065 USA

[2] Merck Res Labs, Dept Pharmacol, Rahway, NJ 07065 USA

[3] Merck Res Labs, Dept Metab Disorders & Mol Endocrinol, Rahway, NJ 07065 USA

[4] Merck Res Labs, Lab Anim Resourcesd, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 01期

关键词：

Glucagon receptor antagonists; Pyrazole; Diabetes; GLUCOSE; RATS; MICE;

D O I：

10.1016/j.bmcl.2010.11.074

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed orally, compound 26 is efficacious in suppressing glucagon induced plasma glucose excursion in rhesus monkey and transgenic murine pharmacodynamic models at 1 and 10 mpk, respectively. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：76 / 81

页数：6

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