Journal of Medicinal Chemistry 2006-07-13

Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder. Synthesis and activity of functionalized glutaramides.

David C Pryde, Graham N Maw, Simon Planken, Michelle Y Platts, Vivienne Sanderson, Martin Corless, Alan Stobie, Christopher G Barber, Rachel Russell, Laura Foster, Laura Barker, Christopher Wayman, Piet Van Der Graaf, Peter Stacey, Debbie Morren, Christopher Kohl, Kevin Beaumont, Sara Coggon, Michael Tute

文献索引：J. Med. Chem. 49 , 4409, (2006)

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摘要

Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and SAR investigations are detailed. In particular, the strategy of starting with the clinically precedented selective NEP inhibitor, Candoxatrilat, and targeting low molecular weight and relatively polar mono-carboxylic acids is described. This led ultimately to the prototype development candidate R-13, for which detailed pharmacology and pharmacokinetic parameters are presented.(1)