Discovery and Exploration of Novel Somatostatin Receptor Subtype 5 (SSTR5) Antagonists for the Treatment of Cholesterol Gallstones


European Journal of Medicinal Chemistry 264, no. December 2023 (2024): 116017


Fanghui Han, Tingting Zhao, Yanglong Zhang, Ying Yun, Yuanyuan Xu, Shimeng Guo, Yongqing Zhong, Xin Xie, and Jianhua Shen



The shortage of cholesterol gallstones treatment intensifies the need to discover of effective small molecule drugs. Clinical follow-up and studies have found that activation of somatostatin receptor subtype 5 (SSTR5) reduce gallbladder contraction and thus increase the risk of cholesterol gallstones, implying that antagonizing SSTR5 may promote gallbladder emptying and reduce the formation of gallstones. Herein, we discovered novel SSTR5 antagonists and firstly investigated its effects on cholesterol gallstone. From loperamide, a reported seed structure with micromole activity, we identified optimal compound 23 as an SSTR5 antagonist exhibiting single-digit nanomolar potency, low hERG inhibition and oral availability. Further in vivo evaluation revealed that 23 significantly promoted gallbladder emptying. Moreover, in a mouse cholesterol gallstone model, 23 (3 mg/kg) effectively reduced the cholesterol gallstones formation, showing better efficacy than the clinical first-line drug UDCA (60 mg/kg), providing a new insight into the development of anti-gallstone drugs.


Keywords: Q4 2023

Go to journal

Get in Touch

We strive to provide the best for our customers, and we are always ready to help. Please let us know if you have a question for us.

Follow us