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Structure-Based Discovery of Novel and Selective 5-Hydroxytryptamine 2B Receptor Antagonists for the Treatment of Irritable Bowel Syndrome.
- 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.
- Subjects :
- Amino Acid Sequence
Animals
CHO Cells
Cricetinae
Cricetulus
Crystallography, X-Ray
Drug Design
Drug Evaluation, Preclinical
Models, Molecular
Molecular Sequence Data
Protein Binding
Rats
Structure-Activity Relationship
Irritable Bowel Syndrome drug therapy
Receptor, Serotonin, 5-HT2B drug effects
Serotonin 5-HT2 Receptor Antagonists chemical synthesis
Serotonin 5-HT2 Receptor Antagonists therapeutic use
Subjects
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