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Bioorg Med Chem Lett. 2011 Oct 1;21(19):5684-7. doi: 10.1016/j.bmcl.2011.08.038. Epub 2011 Aug 12.

Discovery of PF-184563, a potent and selective V1a antagonist for the treatment of dysmenorrhoea. The influence of compound flexibility on microsomal stability.

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Pfizer Worldwide Medicinal Chemistry, Ramsgate Road, Sandwich Kent CT139NJ, UK.


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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