title: Aminopyrazole-Phenylalanine Based GPR142 Agonists: Discovery of Tool Compound and in Vivo Efficacy Studies.
abstract: Herein, we report the lead optimization of amrinone-phenylalanine based GPR142 agonists. Structure-activity relationship studies led to the discovery of aminopyrazole-phenylalanine carboxylic acid 22, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability. Compound 22, together with its orally bioavailable ethyl ester prodrug 23, were found to be suitable for in vivo proof-of-concept studies. Compound 23 displayed good efficacy in a mouse oral glucose tolerance test (OGTT). Compound 22 showed GPR142 dependent stimulation of insulin secretion in isolated mouse islets and demonstrated a statistically significant glucose lowering effect in a mouse model bearing transplanted human islets.
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Mike
authors.initials: M
authors.lastname: Lizarzaburu
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Alykhan
authors.initials: A
authors.lastname: Motani
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Zice
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Du
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jiwen Jim
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Xianyun
authors.initials: X
authors.lastname: Jiao
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: SuJen
authors.initials: S
authors.lastname: Lai
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Fan
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Angela
authors.initials: A
authors.lastname: Fu
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Daiichi-Sankyo , 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710; 1-16-13 Kitakasai, Edogawa-Ku, Tokyo 134-8650, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Murakoshi
authors.affiliation: Daiichi-Sankyo , 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710; 1-16-13 Kitakasai, Edogawa-Ku, Tokyo 134-8650, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Nara
authors.affiliation: Daiichi-Sankyo , 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710; 1-16-13 Kitakasai, Edogawa-Ku, Tokyo 134-8650, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Oda
authors.affiliation: Daiichi-Sankyo , 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710; 1-16-13 Kitakasai, Edogawa-Ku, Tokyo 134-8650, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Okuyama
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jeff D
authors.initials: JD
authors.lastname: Reagan
authors.affiliation: Daiichi-Sankyo , 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710; 1-16-13 Kitakasai, Edogawa-Ku, Tokyo 134-8650, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Daiichi-Sankyo , 1-2-58 Hiromachi, Shinagawa-Ku, Tokyo 140-8710; 1-16-13 Kitakasai, Edogawa-Ku, Tokyo 134-8650, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Run
authors.initials: R
authors.lastname: Zhuang
authors.affiliation: 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: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Houze
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
authors.affiliation: Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Leping
authors.initials: L
authors.lastname: Li
keywords: GPR142 agonist; aminopyrazole−phenylalanine; human islet transplant; insulin secretagogue; oral glucose tolerance test; prodrug; type 2 diabetes