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

David D Manning, Cheng Guo, Zhenjun Zhang, Kristen N Ryan, Jennifer Naginskaya, Sok Hui Choo, Liaqat Masih, William G Earley, Jonathan D Wierschke, Amy S Newman, Catherine A Brady, Nicholas M Barnes, Peter R Guzzo

    Research output: Contribution to journalArticlepeer-review

    5 Citations (Scopus)


    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.

    Original languageEnglish
    Pages (from-to)2578-81
    Number of pages4
    JournalBioorganic & Medicinal Chemistry Letters
    Issue number11
    Publication statusPublished - 1 Jun 2014

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