2. Academic Validation
  3. Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists

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

Affiliation

  • 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.

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