Design of G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) soft drugs with reduced gallbladder-filling effects

The G-protein-coupled bile acid receptor TGR5 agonists were widely developed in type 2 diabetes and gastrointestinal disorders, but were also full of challenges, due to the systemic on-targeted side effects, especially the gallbladder-filling effects. Here, to circumvent these risks, several TGR5 agonists with soft-drug designation had been designed and synthesized with the properties of rapid metabolized after drug effect. Among them, compound 19 showed negligible systemic exposure and favorable gallbladder safety on a 3-day continuous administration, providing a novel strategy for developing TGR5 agonists. [Display omitted] •Soft-drug TGR5 agonists were first designed, synthesized and evaluated.•19 could be rapidly metabolized into inactive metabolite after exerting efficacy.•19 showed negligible systemic exposure and favorable gallbladder safety.•Soft drug strategy is a novel strategy for the development of TGR5 agonists.