2. Academic Validation
  3. 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

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

Affiliation

  • 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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