Design, Synthesis, and Biological Evaluation of Covalently Mucoadhesive Derivatives as Nonsystemic Intestine-Targeted TGR5 Agonists

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Takeda G-protein-coupled receptor 5 (TGR5) is considered a promising therapeutic target for treating type 2 diabetes mellitus (T2DM), obesity, and other metabolism-related diseases. Although many TGR5 agonists have been identified, they might cause some side effects in the gallbladder and the heart. To reduce these side effects and improve glucose-lowering capability, we first designed and synthesized a series of 4-phenoxynicotinamide intestine-targeted TGR5 agonist derivatives containing maleimides in the side chains with different linker lengths. All of the target compounds demonstrated significant TGR5 agonistic activity, among which compound