title: 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.
authors: Genito-Urinary Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent, UK. paul.brennan@pfizer.com
authors: Paul E
authors: PE
authors: Brennan
authors: Gavin A
authors: GA
authors: Whitlock
authors: Danny K H
authors: DK
authors: Ho
authors: Kelly
authors: K
authors: Conlon
authors: Gordon
authors: G
authors: McMurray
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014162:Transfection; D014549:Urinary Incontinence / Q000188:drug therapy*
chemical_list: D001381:Azepines; D011743:Pyrimidines; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011994:Recombinant Proteins; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists