Discovery and exploration of novel somatostatin receptor subtype 5 (SSTR5) antagonists for the treatment of cholesterol gallstones

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

doi:10.1016/j.ejmech.2023.116017

Discovery and exploration of novel somatostatin receptor subtype 5 (SSTR5) antagonists for the treatment of cholesterol gallstones

Eur J Med Chem. 2024 Jan 15:264:116017. doi: 10.1016/j.ejmech.2023.116017. Epub 2023 Dec 5.

Authors

Fanghui Han¹, Tingting Zhao², Yanglong Zhang¹, Ying Yun³, Yuanyuan Xu², Shimeng Guo⁴, Yongqing Zhong⁵, Xin Xie⁶, Jianhua Shen⁷

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
² School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China.
³ School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmacy, Nanchang University, Nanchang, 330000, Jiangxi Province, China.
⁶ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China. Electronic address: xxie@simm.ac.cn.
⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China. Electronic address: jhshen@simm.ac.cn.

PMID: 38070432
DOI: 10.1016/j.ejmech.2023.116017

Abstract

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: Cholesterol gallstones; Gallbladder emptying; SSTR5 antagonist.

MeSH terms

Animals
Cholesterol
Gallstones* / drug therapy
Mice
Receptors, Somatostatin

Substances

Receptors, Somatostatin
Cholesterol