用于治疗2型糖尿病的GPR40激动剂：生物学特性与化学空间
GPR40 agonists for the treatment of type 2 diabetes mellitus: The biological characteristics and the chemical space.
作者信息
Chen Cheng, Li He, Long Ya-Qiu
机构信息
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.
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
出版信息
Bioorg Med Chem Lett. 2016 Dec 1;26(23):5603-5612. doi: 10.1016/j.bmcl.2016.10.074. Epub 2016 Oct 26.
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.
GPR40属于G蛋白偶联受体（GPCR）家族，研究表明，GPR40的激活可诱导胰腺β细胞分泌葡萄糖刺激的胰岛素（GSIS），以及肠道内分泌细胞分泌肠促胰岛素。因此，GPR40已成为治疗2型糖尿病（T2DM）的一个可行且有前景的治疗靶点，且无低血糖风险。然而，TAK - 875因肝毒性问题终止III期临床试验，这让人对靶向GPR40的长期安全性产生怀疑。在此，我们总结了新披露的GPR40激动剂的生物学特性以及基于类药性质的结构演变，以推进基于GPR40的抗糖尿病药物的研发。
Zotero 插件