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.