title: 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.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories,Merck & Co, Inc, Rahway, New Jersey 07065-0900, USA. mail: hong_shen@merck.com
authors.forename: Hong C
authors.initials: HC
authors.lastname: Shen
authors.forename: Fa-Xiang
authors.initials: FX
authors.lastname: Ding
authors.forename: Subharekha
authors.initials: S
authors.lastname: Raghavan
authors.forename: Qiaolin
authors.initials: Q
authors.lastname: Deng
authors.forename: Silvi
authors.initials: S
authors.lastname: Luell
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Forrest
authors.forename: Ester
authors.initials: E
authors.lastname: Carballo-Jane
authors.forename: Larissa C
authors.initials: LC
authors.lastname: Wilsie
authors.forename: Mihajlo L
authors.initials: ML
authors.lastname: Krsmanovic
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Taggart
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
authors.forename: Tsuei-Ju
authors.initials: TJ
authors.lastname: Wu
authors.forename: Kang
authors.initials: K
authors.lastname: Cheng
authors.forename: Ning
authors.initials: N
authors.lastname: Ren
authors.forename: Tian-Quan
authors.initials: TQ
authors.lastname: Cai
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Junying
authors.initials: J
authors.lastname: Wang
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolff
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Tom G
authors.initials: TG
authors.lastname: Holt
authors.forename: M Gerard
authors.initials: MG
authors.lastname: Waters
authors.forename: Milton L
authors.initials: ML
authors.lastname: Hammond
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
mesh_terms: 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
chemical_list: 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