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.
Andrews MD., Fish PV., Blagg J., Brabham TK., Brennan PE., Bridgeland A., Brown AD., Bungay PJ., Conlon KM., Edmunds NJ., af Forselles K., Gibbons CP., Green MP., Hanton G., Holbrook M., Jessiman AS., McIntosh K., McMurray G., Nichols CL., Root JA., Storer RI., Sutton MR., Ward RV., Westbrook D., Whitlock GA.
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.