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. Epub 2011 Aug 12.

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.

MeSH terms

  • Antidiuretic Hormone Receptor Antagonists*
  • Benzodiazepines / chemical synthesis*
  • Benzodiazepines / chemistry
  • Benzodiazepines / metabolism
  • Benzodiazepines / pharmacology*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Design*
  • Drug Discovery*
  • Drug Stability
  • Dysmenorrhea / drug therapy*
  • Female
  • Hormone Antagonists / chemical synthesis*
  • Hormone Antagonists / chemistry
  • Hormone Antagonists / metabolism
  • Hormone Antagonists / pharmacology*
  • Humans
  • Microsomes / physiology
  • Molecular Structure
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / metabolism
  • Triazoles / pharmacology*

Substances

  • Antidiuretic Hormone Receptor Antagonists
  • Hormone Antagonists
  • PF-184563
  • Triazoles
  • Benzodiazepines
  • Cytochrome P-450 Enzyme System