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Validation of Therapeutic Agent Conjugation to Polyvinyl Alcohol-Coated Medical Devices
Published on: November 29, 2024
Design, Synthesis, and Biological Evaluation of Covalently Mucoadhesive Derivatives as Nonsystemic Intestine-Targeted
Shizhen Zhao1,2, Le Wang2, Xiaotong Huang1
1The First Affiliated Hospital of Henan University, Kaifeng 475000, China.
Abstract:
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.
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