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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 |
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| Authors: | Andrews Mark D Fish Paul V Blagg Julian Brabham Tiffini K Brennan Paul E Bridgeland Alison Brown Alan D Bungay Peter J Conlon Kelly M Edmunds Nicholas J af Forselles Kerry Gibbons Colleen P Green Martin P Hanton Giles Holbrook Mark Jessiman Alan S McIntosh Karin McMurray Gordon Nichols Carly L Root James A Storer R Ian Sutton Michael R Ward Robin V Westbrook Dominique Whitlock Gavin A |
| Institution: | a Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK b Drug Safety Research & Development, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK c Genitourinary Biology, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK d Pharmacokinetics, Dynamics & Metabolism, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK e CVMED Biology, Pfizer Global Research and Development, Groton laboratories, 558 Eastern Point Road, Groton, CT 06340, USA f Pharmaceutical Sciences, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent CT13 9NJ, UK |
| Abstract: | New pyrimido4,5-d]azepines 7 are disclosed as potent 5-HT2C receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT2A or 5-HT2B 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. |
| Keywords: | Pyrimido[4 5-d]azepines 5-HT2C receptor agonists PF-3246799 Urinary incontinence |
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