title: Discovery of biaryl anthranilides as full agonists for the high affinity niacin receptor.
abstract: Biaryl anthranilides are reported as potent and selective full agonists for the high affinity niacin receptor GPR109A. The SAR presented outlines approaches to reduce serum shift and both CYPCYP2C8 and CYP2C9 liabilities, while improving PK and maintaining excellent receptor activity. Compound 2i exhibited good in vivo antilipolytic efficacy while providing a significantly improved therapeutic index over vasodilation (flushing) with respect to niacin in the mouse model.
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065-0900, USA. 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: 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: 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: 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: Ning
authors.initials: N
authors.lastname: Ren
authors.forename: Tian-Quan
authors.initials: TQ
authors.lastname: Cai
authors.forename: Qiaolin
authors.initials: Q
authors.lastname: Deng
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: D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011978:Receptors, Nicotinic; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000577:Amides; C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D062367:ortho-Aminobenzoates; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8