The discovery of diazepinone-based 5-HT3 receptor partial agonists
| Autor: | Cheng Guo, Liaqat Masih, David D. Manning, Peter R. Guzzo, Kristen N. Ryan, Jonathan D. Wierschke, Sok Hui Choo, William G. Earley, Nicholas M. Barnes, Zhenjun Zhang, Jennifer Naginskaya, Amy S Newman, Catherine A. Brady |
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| Rok vydání: | 2014 |
| Předmět: |
Clinical Biochemistry
Pharmaceutical Science Administration Oral Pharmacology Biochemistry Partial agonist 5-HT3 receptor Irritable Bowel Syndrome Mice Structure-Activity Relationship Drug Discovery Animals Humans Receptor Molecular Biology 5-HT receptor ADME biology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry HEK 293 cells Azepines Symptomatic relief Disease Models Animal HEK293 Cells biology.protein Molecular Medicine Serotonin Receptors Serotonin 5-HT3 |
| Zdroj: | Bioorganicmedicinal chemistry letters. 24(11) |
| ISSN: | 1464-3405 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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