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New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) 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.

Original publication




Journal article


Bioorg Med Chem Lett

Publication Date





2715 - 2720


Animals, Azepines, Disease Models, Animal, Dogs, Male, Molecular Structure, Pyrimidines, Rats, Serotonin 5-HT2 Receptor Agonists, Urinary Incontinence