GPR40 agonists for the treatment of type 2 diabetes mellitus: The biological characteristics and the chemical space

Bioorg Med Chem Lett. 2016 Dec 1;26(23):5603-5612. doi: 10.1016/j.bmcl.2016.10.074.

Cheng Chen ¹, He Li ², Ya-Qiu Long ³

Affiliations

1 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; Department of Chemistry, Shanghai University, 99 Shangda Road, Shanghai 200444, China.
2 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
3 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: yqlong@simm.ac.cn.

PMID: 27825762 DOI: 10.1016/j.bmcl.2016.10.074

Abstract

GPR40 belongs to the GPCR family and the activation of GPR40 has been shown to induce glucose-stimulated Insulin secretion (GSIS) from pancreatic beta cells as well as incretin secretion from intestinal endocrine cells. Therefore, GPR40 has emerged as a viable and promising therapeutic target for type 2 diabetes mellitus (T2DM) without the risk of hypoglycemia. However, the termination of TAK-875 in phase III clinical trials for the hepatotoxicity issue threw doubt over the long-term safety of targeting GPR40. Herein, we summarized the newly disclosed biological characteristics and the druglikeness-based structural evolution of GPR40 agonists to advance the development of GPR40-based anti-diabetic drugs.

Keywords

Biased agonism; FFA1; GPR40; Glucose-stimulated insulin secretion; Type 2 diabetes.

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