title: Discovery of novel tricyclic full agonists for the G-protein-coupled niacin receptor 109A with minimized flushing in rats.
abstract: Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.
authors.affiliation: Departments of Medicinal Chemistry, 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: Qiaolin
authors.initials: Q
authors.lastname: Deng
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: Ester
authors.initials: E
authors.lastname: Carballo-Jane
authors.forename: Ning
authors.initials: N
authors.lastname: Ren
authors.forename: Tian-Quan
authors.initials: TQ
authors.lastname: Cai
authors.forename: Tsuei-Ju
authors.initials: TJ
authors.lastname: Wu
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
authors.forename: Kang
authors.initials: K
authors.lastname: Cheng
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
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: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003516:Cycloparaffins / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D004423:Ear / Q000098:blood supply; D005483:Flushing / Q000139:chemically induced*; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008066:Lipolysis; D008297:Male; D051379:Mice; D009525:Niacin / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011978:Receptors, Nicotinic; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects; D062367:ortho-Aminobenzoates / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D003516:Cycloparaffins; C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; D006575:Heterocyclic Compounds, 3-Ring; D000960:Hypolipidemic Agents; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D062367:ortho-Aminobenzoates; D009525:Niacin