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Structure-Based Discovery of Novel and Selective 5-Hydroxytryptamine 2B Receptor Antagonists for the Treatment of Irritable Bowel Syndrome.

Authors :
Zhou Y
Ma J
Lin X
Huang XP
Wu K
Huang N
Source :
Journal of medicinal chemistry [J Med Chem] 2016 Jan 28; Vol. 59 (2), pp. 707-20. Date of Electronic Publication: 2016 Jan 07.
Publication Year :
2016

Abstract

Here we employed structure-based ligand discovery techniques to explore a recently determined crystal structure of the 5-hydroxytryptamine 2B (5-HT2B) receptor. Ten compounds containing a novel chemical scaffold were identified; among them, seven molecules were active in cellular function assays with the most potent one exhibiting an IC50 value of 27.3 nM. We then systematically probed the binding characteristics of this scaffold by designing, synthesizing, and testing a series of structural modifications. The structure-activity relationship studies strongly support our predicted binding model. The binding profiling across a panel of 11 5-HT receptors indicated that these compounds are highly selective for the 5-HT2B receptor. Oral administration of compound 15 (30 mg/kg) produced significant attenuation of visceral hypersensitivity in a rat model of irritable bowel syndrome (IBS). We expect this novel scaffold will serve as the foundation for the development of 5-HT2B antagonists for the treatment of IBS.

Details

Language :
English
ISSN :
1520-4804
Volume :
59
Issue :
2
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
26700945
Full Text :
https://doi.org/10.1021/acs.jmedchem.5b01631