Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India.
Department of Pharmaceutical Chemistry, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, Maharashtra, India.
Expert Opin Ther Pat. 2022 Feb;32(2):191-209. doi: 10.1080/13543776.2022.1994551. Epub 2021 Dec 22.
A cell surface bile acid receptor TGR5 is expressed in various tissues, including the liver, kidney, intestine, and adrenal glands, causing its effect in each tissue to differ. A major role for TGR5 is to maintain blood sugar levels and increase in energy expenditure. These benefits make it a potential candidate for the treatment of type 2 diabetes, obesity, and other metabolic diseases.
This paper highlights recent advances in the development of potent steroidal and non-steroidal TGR5 agonists and the peer-reviewed scientific articles that have led to understanding the structure-activity relationship for TGR5 agonists (2012-2020). The review also discusses the clinical progress made by some TGR5 agonists over the past eight years.
In preclinical studies, TGR5 has been found to play a crucial role in GLP-1 secretion and has shown promise for weight loss, anti-diabetic outcomes etc. Semi synthetic and synthetic derivatives can be considered a potential avenue for discovering novel TGR5 agonists. Currently, few TGR5 agonists have reached the clinical trial stage, and, likely, soon novel TGR5 modulator will be discovered with fewer adverse effects. In silico studies can also be performed with various heterocyclic scaffolds to discover selective and safe TGR5 agonists.
一种细胞表面胆汁酸受体 TGR5 表达于多种组织中，包括肝脏、肾脏、肠道和肾上腺，这导致其在每种组织中的作用不同。TGR5 的主要作用是维持血糖水平并增加能量消耗。这些益处使其成为治疗 2 型糖尿病、肥胖症和其他代谢疾病的潜在候选药物。
本文重点介绍了近年来强效甾体和非甾体 TGR5 激动剂的开发进展，以及导致理解 TGR5 激动剂结构-活性关系的同行评议科学文章（2012-2020 年）。该综述还讨论了过去八年中一些 TGR5 激动剂在临床方面取得的进展。
在临床前研究中，TGR5 被发现在 GLP-1 分泌中发挥着关键作用，并且在减肥、抗糖尿病等方面显示出了潜力。半合成和合成衍生物可以被认为是发现新型 TGR5 激动剂的潜在途径。目前，少数 TGR5 激动剂已经进入临床试验阶段，很可能很快就会发现具有较少副作用的新型 TGR5 调节剂。还可以通过各种杂环支架进行计算机研究，以发现选择性和安全性 TGR5 激动剂。
