title: Discovery of a second generation agonist of the orphan G-protein coupled receptor GPR119 with an improved profile.
abstract: The design and synthesis of a second generation GPR119-agonist clinical candidate for the treatment of diabetes is described. Compound 16 (APD597, JNJ-38431055) was selected for preclinical development based on a good balance between agonist potency, intrinsic activity and in particular on its good solubility and reduced drug-drug interaction potential. In addition, extensive in vivo studies showed a more favorable metabolic profile that may avoid the generation of long lasting metabolites with the potential to accumulate in clinical studies.
authors.affiliation: Medicinal Chemistry, Arena Pharmaceuticals, San Diego, CA 92121, USA. GSemple@arenapharm.com
authors.forename: Graeme
authors.initials: G
authors.lastname: Semple
authors.forename: Juerg
authors.initials: J
authors.lastname: Lehmann
authors.forename: Amy
authors.initials: A
authors.lastname: Wong
authors.forename: Albert
authors.initials: A
authors.lastname: Ren
authors.forename: Marc
authors.initials: M
authors.lastname: Bruce
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Shin
authors.forename: Carleton R
authors.initials: CR
authors.lastname: Sage
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Chen
authors.forename: Kristen
authors.initials: K
authors.lastname: Sebring
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Chu
authors.forename: James N
authors.initials: JN
authors.lastname: Leonard
authors.forename: Hussein
authors.initials: H
authors.lastname: Al-Shamma
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grottick
authors.forename: Fuyong
authors.initials: F
authors.lastname: Du
authors.forename: Yin
authors.initials: Y
authors.lastname: Liang
authors.forename: Keith
authors.initials: K
authors.lastname: Demarest
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jones
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D055808:Drug Discovery; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics*; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
chemical_list: C572261:APD597; C519854:GPR119 protein, human; D007004:Hypoglycemic Agents; D010880:Piperidines; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled