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 niacin regarding the FFA reduction versus vasodilation in rats and dogs.
Shen
Hong C
HC
Department of Medicinal Chemistry, Merck Research Laboratories,Merck & Co, Inc, Rahway, New Jersey 07065-0900, USA. mail: hong_shen@merck.com
Ding
Fa-Xiang
FX
Raghavan
Subharekha
S
Deng
Qiaolin
Q
Luell
Silvi
S
Forrest
Michael J
MJ
Carballo-Jane
Ester
E
Wilsie
Larissa C
LC
Krsmanovic
Mihajlo L
ML
Taggart
Andrew K
AK
Wu
Kenneth K
KK
Wu
Tsuei-Ju
TJ
Cheng
Kang
K
Ren
Ning
N
Cai
Tian-Quan
TQ
Chen
Qing
Q
Wang
Junying
J
Wolff
Michael S
MS
Tong
Xinchun
X
Holt
Tom G
TG
Waters
M Gerard
MG
Hammond
Milton L
ML
Tata
James R
JR
Colletti
Steven L
SL
D000818:Animals; D019540:Area Under Curve; D001667:Binding, Competitive; D016466:CHO Cells; D002264:Carboxylic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D003509:Cyclohexanecarboxylic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D053138:Cyclohexenes / Q000737:chemistry*; D004285:Dogs; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008956:Models, Chemical; D015394:Molecular Structure; D010069:Oxadiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects
D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D005230:Fatty Acids, Nonesterified; C530636:HCAR2 protein, human; C549062:MK 6892; D010069:Oxadiazoles; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; C052568:cyclohexene