Bharate Sandip B, Nemmani Kumar V S, Vishwakarma Ram A
Department of Medicinal Chemistry & Pharmacology, Piramal Life Sciences Limited, Goregaon, Mumbai, India.
Expert Opin Ther Pat. 2009 Feb;19(2):237-64. doi: 10.1517/13543770802665717.
The family of G-protein-coupled receptors (GPCRs) serves as the target for almost a third of currently marketed drugs and provides the predominant mechanism through which extracellular factors transmit signals to the cell. GPCRs have been proved to be good therapeutic targets for metabolic disorders. In recent years, a number of companies have been actively involved in the discovery of small-molecule modulators of the GPR40 (FFA1) receptor. However, to date, no critical, comprehensive review on small-molecule modulators of GPR40 (FFA1) has been published.
To review the discovery and development of small-molecule GPR40 (FFA1) agonists/antagonists by different research groups and to classify them based on the key structural features.
Systematic search, analysis, and summary of the publication and patent literature for small-molecule modulators of the GPR40 (FFA1) receptor to June 2008. The patent information for this review is drawn from the Integrity Prous, Scifinder, Esp@cenet, and freepatentonline.com databases.
The para-substituted phenyl propionic acid scaffold has emerged as a common structural motif found in many GPR40 (FFA1) agonists, and compounds having an aromatic ring and a group capable of releasing a cation have exhibited excellent GPR40 (FFA1) agonistic activity. Several small-molecule agonists of GPR40 (FFA1) have been discovered, which offer a great promise in the treatment of type 2 diabetes.
G蛋白偶联受体（GPCRs）家族是目前近三分之一上市药物的作用靶点，是细胞外因子向细胞传递信号的主要机制。GPCRs已被证明是治疗代谢紊乱的良好靶点。近年来，多家公司积极参与GPR40（FFA1）受体小分子调节剂的研发。然而，迄今为止，尚未发表关于GPR40（FFA1）小分子调节剂的重要、全面综述。
综述不同研究小组对GPR40（FFA1）小分子激动剂/拮抗剂的发现与开发，并根据关键结构特征对其进行分类。
系统检索、分析和总结截至2008年6月关于GPR40（FFA1）受体小分子调节剂的出版物和专利文献。本综述的专利信息来自Integrity Prous、Scifinder、Esp@cenet和freepatentonline.com数据库。
对-取代苯基丙酸支架已成为许多GPR40（FFA1）激动剂中常见的结构基序，具有芳环和能够释放阳离子基团的化合物表现出优异的GPR40（FFA1）激动活性。已发现几种GPR40（FFA1）小分子激动剂，在2型糖尿病治疗中具有巨大潜力。
