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

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.