Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles

  • ACS Med Chem Lett. 2013 May 7;4(6):551-5. doi: 10.1021/ml300427u.
Yingcai Wang  1 Jiwen Jim Liu  1 Paul J Dransfield  1 Liusheng Zhu  1 Zhongyu Wang  1 Xiaohui Du  1 Xianyun Jiao  1 Yongli Su  1 An-Rong Li  1 Sean P Brown  1 Annie Kasparian  1 Marc Vimolratana  1 Ming Yu  1 Vatee Pattaropong  1 Jonathan B Houze  1 Gayathri Swaminath  1 Thanhvien Tran  1 Khanh Nguyen  1 Qi Guo  1 Jane Zhang  1 Run Zhuang  1 Frank Li  1 Lynn Miao  1 Michael D Bartberger  1 Tiffany L Correll  1 David Chow  1 Simon Wong  1 Jian Luo  1 Daniel C-H Lin  1 Julio C Medina  1
Affiliations
  • 1. 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.
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.

Keywords
AM-1638; AM-5262; AMG 837; FFA1; FFAR1; GPR40; full agonist; spirocycles; tricyclic.
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