The discovery of diazepinone-based 5-HT3 receptor partial agonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 11; pp. 2578 - 2581
• Main Authors: Manning, David D., Guo, Cheng, Zhang, Zhenjun, Ryan, Kristen N., Naginskaya, Jennifer, Choo, Sok Hui, Masih, Liaqat, Earley, William G., Wierschke, Jonathan D., Newman, Amy S., Brady, Catherine A., Barnes, Nicholas M., Guzzo, Peter R.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2014
• Subjects: 5-HT3 receptor partial agonist; Administration, Oral; Alosetron; Animals; Azepines - administration & dosage; Azepines - chemistry; Azepines - pharmacology; Diazepinone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; HEK293 Cells; Humans; Irritable bowel syndrome (IBS); Irritable Bowel Syndrome - drug therapy; Ligand-gated ion channel; Mice; Molecular Structure; Ramosetron; Receptors, Serotonin, 5-HT3 - metabolism; Structure-Activity Relationship; Diazepinone; Ramosetron; 5-HT3 receptor partial agonist; Irritable bowel syndrome (IBS); Ligand-gated ion channel; Alosetron; 5-HT receptor partial agonist
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.03.074

Serotonin type 3 receptor partial agonists with nanomolar binding affinity and low to moderate intrinsic activity (IA=7–87% of 5-HT Emax) are described. Oral activity and favorable drug properties are provided for select compounds. Serotonin type 3 (5-HT3) receptor partial agonists have been targeted as potential new drugs for the symptomatic relief of irritable bowel syndrome (IBS). Multiple diazepinone-based compounds have been discovered, which exhibit nanomolar binding affinity for the h5-HT3A receptor and display a range of intrinsic activities (IA=7–87% of 5-HT Emax) in HEK cells heterologously expressing the h5-HT3A receptor. Favorable physicochemical properties and in vitro ADME profile coupled with oral activity in the murine von Bezold–Jarisch reflex model demonstrates the series has promise for producing low to moderate IA partial agonists suitable for an IBS indication.