Pyrimido[4,5-d]azepines as potent and selective 5-HT₂C receptor agonists: Design, synthesis, and evaluation of PF-3246799 as a treatment for urinary incontinence

New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT₂C receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT₂A or 5-HT₂B receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.