State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zuchongzhi Road, Shanghai, 201203, China.
Eur J Med Chem. 2022 Nov 15;242:114697. doi: 10.1016/j.ejmech.2022.114697. Epub 2022 Aug 20.
Ulcerative colitis (UC) is a gastrointestinal disease with complex etiology, and the shortage of the treatment further intensifies the need to discover new therapies based on novel mechanisms and strategies. TGR5 and DPP4 are beneficial to treat UC through multiple mechanisms, notably increasing GLP-2 levels by promoting secretion and inhibiting degradation respectively. However, some unwanted systemic effects caused by systemic exposure hinder development, especially the gallbladder-filling effects. Herein, we firstly reported a series of high-potency gut-restricted TGR5-DPP4 bifunctional molecules by gut-restriction and multitarget strategies to utilize the positive impacts of TGR5 and DPP4 on UC and avoid unwanted systemic effects. In particularly, racemic compound 15, a high-potency TGR5-DPP4 bifunctional molecule, showed favorable intestinal distribution, preferable efficacy in mice colitis model and good gallbladder safety. Therefore, the feasibility of gut-restricted TGR5-DPP4 bifunctional molecule was confirmed for the treatment UC, providing a new insight into the development of anti-UC drugs.
溃疡性结肠炎（UC）是一种病因复杂的胃肠道疾病，治疗方法的缺乏进一步加剧了人们对基于新机制和策略的新型疗法的需求。TGR5 和 DPP4 通过多种机制有利于治疗 UC，特别是通过分别促进分泌和抑制降解来增加 GLP-2 水平。然而，全身暴露引起的一些不良全身作用会阻碍其发展，特别是胆囊填充作用。在此，我们首次通过肠道限制和多靶点策略报道了一系列高效的肠道限制 TGR5-DPP4 双功能分子，以利用 TGR5 和 DPP4 对 UC 的积极影响，同时避免不必要的全身作用。特别是，外消旋化合物 15 是一种高效的 TGR5-DPP4 双功能分子，表现出良好的肠道分布、在小鼠结肠炎模型中的优异疗效和良好的胆囊安全性。因此，肠道限制 TGR5-DPP4 双功能分子治疗 UC 的可行性得到了证实，为抗 UC 药物的开发提供了新的思路。
