Discovery of the imidazole-derived GPR40 agonist AM-3189

Zhihua Ma; Daniel C-H Lin; Rajiv Sharma; Jinqian Liu; Liusheng Zhu; An-Rong Li; Todd Kohn; Yingcai Wang; Jiwen Jim Liu; Michael D Bartberger; Julio C Medina; Run Zhuang; Frank Li; Jane Zhang; Jian Luo; Simon Wong; George R Tonn; Jonathan B Houze

doi:10.1016/j.bmcl.2015.11.050

Discovery of the imidazole-derived GPR40 agonist AM-3189

Bioorg Med Chem Lett. 2016 Jan 1;26(1):15-20. doi: 10.1016/j.bmcl.2015.11.050. Epub 2015 Nov 17.

Authors

Zhihua Ma¹, Daniel C-H Lin², Rajiv Sharma¹, Jinqian Liu¹, Liusheng Zhu¹, An-Rong Li¹, Todd Kohn¹, Yingcai Wang¹, Jiwen Jim Liu¹, Michael D Bartberger¹, Julio C Medina¹, Run Zhuang², Frank Li², Jane Zhang², Jian Luo², Simon Wong³, George R Tonn³, Jonathan B Houze¹

Affiliations

¹ Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
² Department of Metabolic Disorders, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
³ Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.

PMID: 26620255
DOI: 10.1016/j.bmcl.2015.11.050

Abstract

As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837.

Keywords: AM-3189; AMG 837; Agonist; FFAR1; GPCR; GPR40; Insulin secretagogue; Type II diabetes.

MeSH terms

Animals
Dogs
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry*
Imidazoles / pharmacology*
Macaca fascicularis
Mice
Molecular Structure
Rats
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship

Substances

AM-3189
FFAR1 protein, human
Imidazoles
Receptors, G-Protein-Coupled
imidazole