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

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.

doi:10.1021/jm100022r.s001

jm100022r_si_001.pdf (12.27 MB)

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

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posted on 2010-03-25, 00:00 authored by Hong C. Shen, Fa-Xiang Ding, Subharekha Raghavan, Qiaolin Deng, Silvi Luell, Michael J. Forrest, Ester Carballo-Jane, Larissa C. Wilsie, Mihajlo L. Krsmanovic, Andrew K. Taggart, Kenneth K. Wu, Tsuei-Ju Wu, Kang Cheng, Ning Ren, Tian-Quan Cai, Qing Chen, Junying Wang, Michael S. Wolff, Xinchun Tong, Tom G. Holt, M. Gerard Waters, Milton L. Hammond, James R. Tata, Steven L. Colletti

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.

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

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