GPR40 agonists for the treatment of type 2 diabetes mellitus: The biological characteristics and the chemical space.
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.
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.
Cheng
C
Chen
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
He
H
Li
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.
Ya-Qiu
YQ
Long
D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D001572:Benzofurans; C473034:FFAR1 protein, human; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C557331:TAK-875
Biased agonism; FFA1; GPR40; Glucose-stimulated insulin secretion; Type 2 diabetes