Discovery of a novel azepine series of potent and selective 5-HT2C agonists as potential treatments for urinary incontinence

A range of heterocycle fused azepines were synthesized in order to find a CNS penetrant, selective 5-HT2C agonist for the treatment of incontinence. The pyridazo-azepines such as compound 11 were shown to be potent 5-HT2C agonists and have potential for CNS penetration and good in vitro ADME properties but lacked selectivity against 5-HT2B. Fusing a further heterocycle gave the selective triazolopyrimido-azepines. An example of this series, compound 36, was shown to be potent, selective, metabolically stable in vitro and efficacious in an in vivo model of stress urinary incontinence.

Graphical abstractFused azepines such as compound 11 were shown to be potent 5-HT2C agonists with the potential for CNS penetration and good in vitro ADME properties. Improved selectivity against the 5-HT2B receptor was achieved with tricyclic analogues such as compound 36.Figure optionsDownload full-size imageDownload as PowerPoint slide