A Multivalent Approach to the Design and Discovery of Orally Efficacious 5-HT₄Receptor Agonists

5-HT4 receptor agonists such as tegaserod have demonstrated efficacy in the treatment of constipation predominant irritable bowel syndrome (IBS-C), a highly prevalent disorder characterized by chronic constipation and impairment of intestinal propulsion, abdominal bloating, and pain. The 5-HT4 receptor binding site can accommodate functionally and sterically diverse groups attached to the amine nitrogen atom of common ligands, occupying what may be termed a "secondary" binding site. Using a multivalent approach to lead discovery, we have investigated how varying the position and nature of the secondary binding group can be used as a strategy to achieve the desired 5-HT4 agonist pharmacological profile. During this study, we discovered the ability of amine-based secondary binding groups to impart exceptional gains in the binding affinity, selectivity, and functional potency of 5-HT4 agonists. Optimization of the leads generated by this approach afforded compound 26, a selective, orally efficacious 5-HT4 agonist for the potential treatment of gastrointestinal motility-related disorders.