title: Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists.
abstract: We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound 8 and 20 also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties.
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: Xiaohui
authors.initials: X
authors.lastname: Du
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: 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: 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: Yingcai
authors.initials: Y
authors.lastname: Wang
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: Zhongyu
authors.initials: Z
authors.lastname: Wang
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: Todd
authors.initials: T
authors.lastname: Kohn
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: Ming
authors.initials: M
authors.lastname: Yu
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: 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: 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: An-Rong
authors.initials: AR
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: Yongli
authors.initials: Y
authors.lastname: Su
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: Jiwen Jim
authors.initials: JJ
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: 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: Thanhvien
authors.initials: T
authors.lastname: Tran
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: 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: 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: 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: Richard
authors.initials: R
authors.lastname: Connors
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: Jonathan B
authors.initials: JB
authors.lastname: Houze
keywords: FFA1; GPR40; full agonist; insulin secretagoue; type 2 diabetes