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

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 22b displayed the best TGR5 agonistic
activity. Additionally, compound 22b displayed low Caco-2
cell permeability and strong mucoadhesion to mucin and the rat intestine.
In C57BL/6J, diet-induced obese, and db/db mice, compound 22b demonstrated a robust and prolonged
hypoglycemic effect along with an acceptable safety profile.