Chemical Research, Merck Research Laboratories, Kenilworth, New Jersey, USA.
Vitam Horm. 2010;84:415-48. doi: 10.1016/B978-0-12-381517-0.00016-3.
Type 2 diabetes (T2D) has reached epidemic proportions, and there is an unmet medical need for orally effective agents that regulate glucose homeostasis. GPR119, a class-A (rhodopsin-like) G protein-coupled receptor expressed primarily in the pancreas and gastrointestinal tract, has attracted considerable interest as a T2D drug target in recent years. The activation of GPR119 increases the intracellular accumulation of cAMP, leading to enhanced glucose-dependent insulin secretion from pancreatic β-cells and increased release of the gut peptides GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic peptide) and PYY (polypeptide YY). Oral administration of small molecule GPR119 agonists has been shown to improve glucose tolerance in both rodents and humans. This review summarizes the research leading to the identification of GPR119 as a potential drug target for T2D and related metabolic disorders, and provides an overview of the recent progress made in the discovery of orally active GPR119 agonists.
2 型糖尿病（T2D）已达到流行程度，对于口服有效且能调节葡萄糖动态平衡的药物存在未满足的医学需求。G 蛋白偶联受体 119（GPR119）是一种 A 类（视紫红质样）G 蛋白偶联受体，主要在胰腺和胃肠道表达，近年来作为 T2D 药物靶点引起了相当大的关注。GPR119 的激活会增加细胞内 cAMP 的积累，从而促进胰腺β细胞中葡萄糖依赖性胰岛素的分泌，并增加肠道肽 GLP-1（胰高血糖素样肽 1）、GIP（葡萄糖依赖性胰岛素释放肽）和 PYY（多肽 YY）的释放。小分子 GPR119 激动剂的口服给药已被证明可改善啮齿动物和人类的葡萄糖耐量。本文总结了将 GPR119 鉴定为 T2D 和相关代谢紊乱的潜在药物靶点的研究进展，并概述了发现口服活性 GPR119 激动剂方面的最新进展。
