National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Acta Pharmacol Sin. 2012 Feb;33(2):148-54. doi: 10.1038/aps.2011.169.
Glucagon-like peptide-1 (GLP-1)-based therapy presents a promising option for treating type 2 diabetes. However, there are several limitations relative to the peptidic GLP-1 mimetics currently on the market or under development. This concern has led to a continued interest in the search for non-peptidic agonists for GLP-1 receptor (GLP-1R). Here, we briefly review the discovery, characterization and current status of a novel class of cyclobutane-derivative-based non-peptidic agonists for GLP-1R, including Boc5 and its newly discovered analogue WB4-24. Although the oral bioavailability of such compounds still poses great challenges, the progress made so far encourages us to identify a truly 'druggable' small molecule agonist for GLP-1R.
胰高血糖素样肽-1(GLP-1)类药物为治疗 2 型糖尿病提供了一种很有前景的选择。然而,目前市场上或正在开发的肽类 GLP-1 类似物存在一些局限性。这种担忧促使人们持续关注寻找非肽类 GLP-1 受体(GLP-1R)激动剂。在这里,我们简要回顾了一类新型基于环丁烷衍生物的非肽类 GLP-1R 激动剂的发现、特性和现状,包括 Boc5 及其新发现的类似物 WB4-24。尽管这类化合物的口服生物利用度仍然存在很大的挑战,但迄今为止取得的进展鼓励我们鉴定出真正可成药的 GLP-1R 小分子激动剂。