title: Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119.
abstract: GPR119 is a rhodopsin-like GPCR expressed in pancreatic beta-cells and incretin releasing cells in the GI tract. As with incretins, GPR119 increases cAMP levels in these cell types, thus making it a highly attractive potential target for the treatment of diabetes. The discovery of the first reported potent agonist of GPR119, 2-fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine (8g, AR231453), is described starting from an initial inverse agonist screening hit. Compound 8g showed in vivo activity in rodents and was active in an oral glucose tolerance test in mice following oral administration.
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: Beatriz
authors.initials: B
authors.lastname: Fioravanti
authors.forename: Guillherme
authors.initials: G
authors.lastname: Pereira
authors.forename: Imelda
authors.initials: I
authors.lastname: Calderon
authors.forename: Jane
authors.initials: J
authors.lastname: Uy
authors.forename: Karoline
authors.initials: K
authors.lastname: Choi
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Xiong
authors.forename: Albert
authors.initials: A
authors.lastname: Ren
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.forename: Vibha
authors.initials: V
authors.lastname: Dave
authors.forename: William
authors.initials: W
authors.lastname: Thomsen
authors.forename: David J
authors.initials: DJ
authors.lastname: Unett
authors.forename: Charles
authors.initials: C
authors.lastname: Xing
authors.forename: Stuart
authors.initials: S
authors.lastname: Bossie
authors.forename: Chris
authors.initials: C
authors.lastname: Carroll
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Chu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grottick
authors.forename: Erin K
authors.initials: EK
authors.lastname: Hauser
authors.forename: James
authors.initials: J
authors.lastname: Leonard
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jones
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; C532423:GPR119 protein, rat; C516207:Gpr119 protein, mouse; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled