Discovery of a Biaryl Cyclohexene Carboxylic Acid (MK-6892): A Potent and Selective High Affinity Niacin Receptor Full Agonist with Reduced Flushing Profiles in Animals as a Preclinical Candidate

被引：49

作者：

Shen, Hong C. ^{[1
]}

Ding, Fa-Xiang ^{[1
]}

Raghavan, Subharekha ^{[1
]}

Deng, Qiaolin ^{[1
]}

Luell, Silvi ^{[2
]}

Forrest, Michael J. ^{[2
]}

Carballo-Jane, Ester ^{[2
]}

Wilsie, Larissa C. ^{[3
]}

Krsmanovic, Mihajlo L. ^{[3
]}

Taggart, Andrew K. ^{[3
]}

Wu, Kenneth K. ^{[3
]}

Wu, Tsuei-Ju ^{[3
]}

Cheng, Kang ^{[3
]}

Ren, Ning ^{[3
]}

Cai, Tian-Quan ^{[3
]}

Chen, Qing ^{[4
]}

Wang, Junying ^{[4
]}

Wolff, Michael S. ^{[4
]}

Tong, Xinchun ^{[4
]}

Holt, Tom G. ^{[4
]}

Waters, M. Gerard ^{[3
]}

Hammond, Milton L. ^{[1
]}

Tata, James R. ^{[1
]}

Colletti, Steven L. ^{[1
]}

机构：

[1] Merck & Co Inc, Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA

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

[3] Merck & Co Inc, Merck Res Labs, Dept Cardiovasc Dis, Rahway, NJ 07065 USA

[4] Merck & Co Inc, Merck Res Labs, Dept Drug Metab, Rahway, NJ 07065 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 06期

关键词：

NICOTINIC-ACID; PUMA-G; LIPOLYSIS; DRUG; RAT;

D O I：

10.1021/jm100022r

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound le (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.

引用

页码：2666 / 2670

页数：5

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