Iminopyrimidinones: a novel pharmacophore for the development of orally active renin inhibitors

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1592-6. doi: 10.1016/j.bmcl.2015.02.003. Epub 2015 Feb 10.

Abstract

The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.

Keywords: BACE1; Enzyme inhibitors; Hypertension; Renin inhibitors; Structure-based drug design.

MeSH terms

  • Administration, Oral
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Imines / chemical synthesis
  • Imines / chemistry
  • Imines / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Renin / antagonists & inhibitors*
  • Renin / metabolism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Imines
  • Pyrimidinones
  • Renin