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.

Abstract

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.

DOI: 10.1016/j.bmcl.2010.11.120

Cite this paper

@article{Andrews2011Pyrimido45dazepinesAP, title={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.}, author={Mark D Andrews and Paul V. Fish and Julian Blagg and Tiffini K Brabham and Paul E Brennan and Alison Bridgeland and Alan D. G. Brown and Peter J Bungay and Kelly M Conlon and Nicholas J Edmunds and Kerry J Af Forselles and Colleen P Gibbons and Martin P Green and Giles Hanton and Mark Holbrook and Alan S Jessiman and Karin McIntosh and Gordon McMurray and Carly L Nichols and James A Root and R. Ian Storer and Michael R. Sutton and Robin Ward and Dominique Westbrook and Gavin A Whitlock}, journal={Bioorganic & medicinal chemistry letters}, year={2011}, volume={21 9}, pages={2715-20} }