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

  • Bioorg Med Chem Lett. 2011 Oct 1;21(19):5684-7. doi: 10.1016/j.bmcl.2011.08.038.
Patrick S Johnson  1 ,  Thomas Ryckmans ,  Justin Bryans ,  Dave M Beal ,  Kevin N Dack ,  Neil Feeder ,  Anthony Harrison ,  Mark Lewis ,  Helen J Mason ,  James Mills ,  Julie Newman ,  Christelle Pasquinet ,  Dave J Rawson ,  Lee R Roberts ,  Rachel Russell ,  Deborah Spark ,  Alan Stobie ,  Toby J Underwood ,  Robin Ward ,  Simon Wheeler
Affiliations
  • 1. Pfizer Worldwide Medicinal Chemistry, Ramsgate Road, Sandwich Kent CT139NJ, UK.
PMID: 21885275 DOI: 10.1016/j.bmcl.2011.08.038
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.