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

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.