2. Academic Validation
  3. Rational Design of Dual-Target Molecules via a Fragment-Merging Strategy: TGR5 Agonism and SSTR5 Antagonism

Rational Design of Dual-Target Molecules via a Fragment-Merging Strategy: TGR5 Agonism and SSTR5 Antagonism

  • J Med Chem. 2026 Apr 23;69(8):8935-8959. doi: 10.1021/acs.jmedchem.5c03308.
Chuhua Song 1 2,  Yu Wang 3 2,  Xiaoyu Han 1 2,  Mengya Li 4,  Shimeng Guo 1,  Lili Chen 1,  Jun Sun 5,  Fanghui Han 1,  Yuqi Shi 1 2,  Jing Hu 1 2,  Jialin Zhao 1 6,  Kai Wang 1,  Xin Xie 1 3 2 5 6 7,  Jianhua Shen 1 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310020, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China.
  • 5 School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 6 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 7 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research, Institute for Drug Discovery, Yantai 264003, China.
PMID: 41941587 DOI: 10.1021/acs.jmedchem.5c03308
Abstract

TGR5 represents a compelling therapeutic target for metabolic disorders, yet the clinical development of its agonists has been constrained by gallbladder filling. Antagonism of SSTR5 enhances GLP-1 secretion and promotes gallbladder contraction signaling, supporting incretin-mediated glycemic control, and counteracting TGR5-mediated gallbladder filling. Guided by this rationale, a series of dual-target small molecules were rationally designed and synthesized to concurrently activate TGR5 and antagonize SSTR5. Among them, compound 19 (hTGR5 EC50 = 5.91 nM; hSSTR5 IC50 = 4.37 nM) exhibited potent and balanced in vitro activity at both TGR5 and SSTR5, although the series displays suboptimal physicochemical and metabolic properties. In vivo, compound 19 improved glucose tolerance and alleviated gallbladder filling at pharmacologically relevant doses. Collectively, these findings establish a proof of concept for dual TGR5/SSTR5 modulation as a promising therapeutic modality, providing a viable strategy to achieve potent metabolic efficacy with reduced risk of adverse effects.

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