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

Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niac...

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Veröffentlicht in:	Journal of medicinal chemistry 2010-03, Vol.53 (6), p.2666-2670
Hauptverfasser:	Shen, Hong C, Ding, Fa-Xiang, Raghavan, Subharekha, Deng, Qiaolin, Luell, Silvi, Forrest, Michael J, Carballo-Jane, Ester, Wilsie, Larissa C, Krsmanovic, Mihajlo L, Taggart, Andrew K, Wu, Kenneth K, Wu, Tsuei-Ju, Cheng, Kang, Ren, Ning, Cai, Tian-Quan, Chen, Qing, Wang, Junying, Wolff, Michael S, Tong, Xinchun, Holt, Tom G, Waters, M. Gerard, Hammond, Milton L, Tata, James R, Colletti, Steven L
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Area Under Curve Binding, Competitive Carboxylic Acids - chemistry Carboxylic Acids - pharmacokinetics Carboxylic Acids - pharmacology CHO Cells Cricetinae Cricetulus Cyclohexanecarboxylic Acids - chemistry Cyclohexanecarboxylic Acids - pharmacokinetics Cyclohexanecarboxylic Acids - pharmacology Cyclohexenes - chemistry Dogs Drug Discovery Drug Evaluation, Preclinical Fatty Acids, Nonesterified - blood Humans Metabolic Clearance Rate Mice Mice, Inbred C57BL Mice, Knockout Models, Chemical Molecular Structure Oxadiazoles - chemistry Oxadiazoles - pharmacokinetics Oxadiazoles - pharmacology Rats Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Receptors, Nicotinic - genetics Receptors, Nicotinic - metabolism Structure-Activity Relationship Vasodilation - drug effects
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Zusammenfassung:	Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm100022r