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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.

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.
Bioorg Med Chem Lett; 21(9): 2715-20, 2011 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21195614
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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