The discovery of diazepinone-based 5-HT3 receptor partial agonists
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 targete...
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Published in | Bioorganic & medicinal chemistry letters Vol. 24; no. 11; pp. 2578 - 2581 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Elsevier Ltd
01.06.2014
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0960-894X 1464-3405 |
DOI: | 10.1016/j.bmcl.2014.03.074 |