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  • Title: Discovery of PF-184563, a potent and selective V1a antagonist for the treatment of dysmenorrhoea. The influence of compound flexibility on microsomal stability.
    Author: Johnson PS, Ryckmans T, Bryans J, Beal DM, Dack KN, Feeder N, Harrison A, Lewis M, Mason HJ, Mills J, Newman J, Pasquinet C, Rawson DJ, Roberts LR, Russell R, Spark D, Stobie A, Underwood TJ, Ward R, Wheeler S.
    Journal: Bioorg Med Chem Lett; 2011 Oct 01; 21(19):5684-7. PubMed ID: 21885275.
    Abstract:
    The V1a receptor has emerged as an attractive target for a range of indications including Raynaud's disease and dysmenorrhoea. As part of an effort to discover a new class of orally active V1a antagonist, we optimised a highly lipophilic, metabolically unstable lead into a range of potent, selective and metabolically stable V1a antagonists. In this communication, we demonstrate the series-dependent effect of limiting the number of rotatable bonds in order to decrease Cytochrome P450-mediated metabolism. This effort culminated in the discovery of PF-184563, a novel, selective V1a antagonist with excellent in vitro and in vivo properties.
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