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

Abstract A range of heterocycle fused azepines were synthesized in order to find a CNS penetrant, selective 5-HT 2C agonist for the treatment of incontinence. The pyridazo-azepines such as compound 11 were shown to be potent 5-HT 2C agonists and have potential for CNS penetration and good in vitro ADME properties but lacked selectivity against 5-HT 2B . 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.