title: Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles.
abstract: GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism leading to little risk of hypoglycemia. We recently reported the discovery of AM-1638 (2), a potent full agonist of GPR40. In this report, we present the discovery of GPR40 full agonists containing conformationally constrained tricyclic spirocycles and their structure-activity relationships leading to more potent agonists such as AM-5262 (26) with improved rat PK profile and general selectivity profile. AM-5262 enhanced glucose stimulated insulin secretion (mouse and human islets) and improved glucose homeostasis in vivo (OGTT in HF/STZ mice) when compared to AM-1638.
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, 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, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, 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, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, 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, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, 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, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Xianyun
authors.initials: X
authors.lastname: Jiao
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: An-Rong
authors.initials: AR
authors.lastname: Li
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, 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, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Annie
authors.initials: A
authors.lastname: Kasparian
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Vimolratana
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Vatee
authors.initials: V
authors.lastname: Pattaropong
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Houze
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, 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, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Thanhvien
authors.initials: T
authors.lastname: Tran
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Khanh
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, 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, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, 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, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, 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, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Lynn
authors.initials: L
authors.lastname: Miao
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Correll
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: David
authors.initials: D
authors.lastname: Chow
authors.affiliation: Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, 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, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, 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, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, 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, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
keywords: AM-1638; AM-5262; AMG 837; FFA1; FFAR1; GPR40; full agonist; spirocycles; tricyclic