title: 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): a partial agonist of the nicotinic acid receptor, G-protein coupled receptor 109a, with antilipolytic but no vasodilatory activity in mice.
abstract: The discovery and profiling of 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (5a, MK-0354), a partial agonist of GPR109a, is described. Compound 5a retained the plasma free fatty acid lowering effects in mice associated with GPR109a agonism, but did not induce vasodilation at the maximum feasible dose. Moreover, preadministration of 5a blocked the flushing effect induced by nicotinic acid but not that induced by PGD2. This profile made 5a a suitable candidate for further study for the treatment of dyslipidemia.
authors.affiliation: Department of Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121, USA. gsemple@arenapharm.com
authors.forename: Graeme
authors.initials: G
authors.lastname: Semple
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Skinner
authors.forename: Tawfik
authors.initials: T
authors.lastname: Gharbaoui
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Shin
authors.forename: Jae-Kyu
authors.initials: JK
authors.lastname: Jung
authors.forename: Martin C
authors.initials: MC
authors.lastname: Cherrier
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Webb
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Tamura
authors.forename: P Douglas
authors.initials: PD
authors.lastname: Boatman
authors.forename: Carleton R
authors.initials: CR
authors.lastname: Sage
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Schrader
authors.forename: Ruoping
authors.initials: R
authors.lastname: Chen
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
authors.forename: M Gerard
authors.initials: MG
authors.lastname: Waters
authors.forename: Kang
authors.initials: K
authors.lastname: Cheng
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Taggart
authors.forename: Tian-Quan
authors.initials: TQ
authors.lastname: Cai
authors.forename: Ester
authors.initials: E
authors.lastname: Carballo-Jane
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Behan
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Connolly
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Richman
mesh_terms: D017667:Adipocytes / Q000187:drug effects; D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006801:Humans; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011720:Pyrazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011978:Receptors, Nicotinic; D013777:Tetrazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014664:Vasodilation / Q000187:drug effects
chemical_list: C531233:3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydrocyclopentapyrazole; D005230:Fatty Acids, Nonesterified; C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; D000960:Hypolipidemic Agents; D011720:Pyrazoles; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D013777:Tetrazoles