Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists

  • ACS Med Chem Lett. 2014 Feb 3;5(4):384-9. doi: 10.1021/ml4005123.
Xiaohui Du  1 ,  Paul J Dransfield  1 ,  Daniel C-H Lin  1 ,  Simon Wong  1 ,  Yingcai Wang  1 ,  Zhongyu Wang  1 ,  Todd Kohn  1 ,  Ming Yu  1 ,  Sean P Brown  1 ,  Marc Vimolratana  1 ,  Liusheng Zhu  1 ,  An-Rong Li  1 ,  Yongli Su  1 ,  Xianyun Jiao  1 ,  Jiwen Jim Liu  1 ,  Gayathri Swaminath  1 ,  Thanhvien Tran  1 ,  Jian Luo  1 ,  Run Zhuang  1 ,  Jane Zhang  1 ,  Qi Guo  1 ,  Frank Li  1 ,  Richard Connors  1 ,  Julio C Medina  1 ,  Jonathan B Houze  1
Affiliations
  • 1. Departments of Therapeutic Discovery, Metabolic Disorders, Pharmaceutics, and Pharmacokinetic and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
PMID: 24900845 DOI: 10.1021/ml4005123
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.

Keywords
FFA1; GPR40; full agonist; insulin secretagoue; type 2 diabetes.