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ID: ALA3259590

Journal: Bioorg Med Chem Lett

Title: The discovery of diazepinone-based 5-HT3 receptor partial agonists.

Authors: Manning DD, Guo C, Zhang Z, Ryan KN, Naginskaya J, Choo SH, Masih L, Earley WG, Wierschke JD, Newman AS, Brady CA, Barnes NM, Guzzo PR.

Abstract: 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.

CiteXplore: 24755431

DOI: 10.1016/j.bmcl.2014.03.074