Novel gut-restricted bivalent agonists targeting mucosal 5-HT4R: Design, synthesis, and biological evaluation

Chronic idiopathic constipation (CIC) is a prevalent gastrointestinal disorder with limited therapeutic options that balance efficacy and safety. Current therapies, such as the 5-HT₄ receptor (5-HT₄R) agonist prucalopride, demonstrate efficacy but are often associated with systemic side effects, highlighting the need for gut-restricted alternatives. Herein, we report for the first time the rational design and synthesis of gut-restricted bivalent agonists targeting mucosal 5-HT₄R by integrating pharmacophores of prucalopride and tenapanor. Structural optimization, particularly of linker length and properties, led to the discovery of compound 4, which exhibited potent 5-HT₄R agonistic activity, high selectivity, and favorable physicochemical properties. Preclinical studies demonstrated that compound 4 significantly enhanced whole-gut and colonic transit, increased fecal output and water content, while maintaining minimal systemic absorption, confirming its gut-restricted nature. These findings underscore the feasibility of gut-restricted 5-HT₄R agonists as a novel therapeutic strategy for CIC and provide valuable insights into the development of safer, more effective treatments for gastrointestinal disorders.