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

  • Bioorg Med Chem Lett. 2011 May 1;21(9):2715-20. doi: 10.1016/j.bmcl.2010.11.120.
Mark D Andrews  1 ,  Paul V Fish ,  Julian Blagg ,  Tiffini K Brabham ,  Paul E Brennan ,  Alison Bridgeland ,  Alan D Brown ,  Peter J Bungay ,  Kelly M Conlon ,  Nicholas J Edmunds ,  Kerry af Forselles ,  Colleen P Gibbons ,  Martin P Green ,  Giles Hanton ,  Mark Holbrook ,  Alan S Jessiman ,  Karin McIntosh ,  Gordon McMurray ,  Carly L Nichols ,  James A Root ,  R Ian Storer ,  Michael R Sutton ,  Robin V Ward ,  Dominique Westbrook ,  Gavin A Whitlock
Affiliations
  • 1. Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK. [email protected]
PMID: 21195614 DOI: 10.1016/j.bmcl.2010.11.120
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.

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