title: Discovery of AM-1638: A Potent and Orally Bioavailable GPR40/FFA1 Full Agonist.
abstract: GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (1), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist 1 to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (21). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist 21 exhibits in BDF/DIO mice as compared to partial agonist 1.
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Brown
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dransfield
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Vimolratana
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: XianYun
authors.initials: X
authors.lastname: Jiao
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Liusheng
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Vatee
authors.initials: V
authors.lastname: Pattaropong
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jinqian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jane
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Simon
authors.initials: S
authors.lastname: Wong
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Run
authors.initials: R
authors.lastname: Zhuang
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Li
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Swaminath
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Daniel C-H
authors.initials: DC
authors.lastname: Lin
authors.affiliation: Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Houze
keywords: AM-1638; AMG 837; FFA1; GPR40; full agonist; insulin secretagogue