title: Discovery of novel orally bioavailable GPR40 agonists.
abstract: The GPR40 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. A series of novel orally bioavailable GPR40 agonists was discovered. SAR study and structural optimization led to identification of compounds 28a and 30a as potent GPR40 agonists with superior physiochemical properties and robust in vivo efficacy in rhesus monkeys.
authors.affiliation: Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China. lvhj@shhrp.com
authors.forename: Hejun
authors.initials: H
authors.lastname: Lu
authors.forename: Hongbo
authors.initials: H
authors.lastname: Fei
authors.forename: Fanglong
authors.initials: F
authors.lastname: Yang
authors.forename: Suxin
authors.initials: S
authors.lastname: Zheng
authors.forename: Qiyue
authors.initials: Q
authors.lastname: Hu
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Jijun
authors.initials: J
authors.lastname: Yuan
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Piaoyang
authors.initials: P
authors.lastname: Sun
authors.forename: Qing
authors.initials: Q
authors.lastname: Dong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001572:Benzofurans; C473034:FFAR1 protein, human; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; D013450:Sulfones; C557331:TAK-875