title: Optimization of GPR40 Agonists for Type 2 Diabetes.
abstract: GPR40 (FFA1 and FFAR1) has gained significant interest as a target for the treatment of type 2 diabetes. TAK-875 (1), a GPR40 agonist, lowered hemoglobin A1c (HbA1c) and lowered both postprandial and fasting blood glucose levels in type 2 diabetic patients in phase II clinical trials. We optimized phenylpropanoic acid derivatives as GPR40 agonists and identified AMG 837 (2) as a clinical candidate. Here we report our efforts in searching for structurally distinct back-ups for AMG 837. These efforts led to the identification of more polar GPR40 agonists, such as AM-4668 (10), that have improved potency, excellent pharmacokinetic properties across species, and minimum central nervous system (CNS) penetration.
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Jiwen Jim
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Yingcai
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Mike
authors.initials: M
authors.lastname: Schmitt
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Liusheng
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Brown
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dransfield
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Run
authors.initials: R
authors.lastname: Zhuang
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Jane
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: George R
authors.initials: GR
authors.lastname: Tonn
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Simon
authors.initials: S
authors.lastname: Wong
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Swaminath
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Daniel C-H
authors.initials: DC
authors.lastname: Lin
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Houze
keywords: FFA1; FFAR1; GPCR; GPR40; agonist; insulin secretagogue; type II diabetes