title: Fluorinated pyrazole acids are agonists of the high affinity niacin receptor GPR109a.
abstract: A series of 5-alkyl pyrazole-3-carboxylic acids were prepared and found to act as potent and selective agonists of the human GPCR, GPR109a, the high affinity nicotinic acid receptor. No activity was observed at the highly homologous low affinity niacin receptor, GPR109b. A further series of 4-fluoro-5-alkyl pyrazole-3-carboxylic acids were shown to display similar potency. One example from the series was shown to have improved properties in vivo compared to niacin.
authors.affiliation: Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. pskinner@arenapharm.com
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Skinner
authors.forename: Martin C
authors.initials: MC
authors.lastname: Cherrier
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Webb
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Shin
authors.forename: Tawfik
authors.initials: T
authors.lastname: Gharbaoui
authors.forename: Andrew
authors.initials: A
authors.lastname: Lindstrom
authors.forename: Vu
authors.initials: V
authors.lastname: Hong
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Tamura
authors.forename: Huong T
authors.initials: HT
authors.lastname: Dang
authors.forename: Cameron C
authors.initials: CC
authors.lastname: Pride
authors.forename: Ruoping
authors.initials: R
authors.lastname: Chen
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Richman
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Connolly
authors.forename: Graeme
authors.initials: G
authors.lastname: Semple
mesh_terms: D000143:Acids / Q000737:chemistry*; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D005461:Fluorine / Q000737:chemistry*; D008024:Ligands; D008297:Male; D051379:Mice; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D013329:Structure-Activity Relationship