Strategies for the modulation of phase II metabolism in a series of PKCε inhibitors

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3398-402. doi: 10.1016/j.bmcl.2014.05.082. Epub 2014 Jun 5.

Abstract

Extensive phase II metabolism of an advanced PKCε inhibitor resulted in sub-optimal pharmacokinetics in rat marked by elevated clearance. Synthesis of the O-glucuronide metabolite as a standard was followed by three distinct strategies to specifically temper phase II metabolic degradation of the parent molecule. In this study, it was determined that the introduction of proximal polarity to the primary alcohol generally curbed O-glucuronidation and improved PK and physical chemical properties while maintaining potency against the target. Utilization of a Jacobsen hydrolytic kinetic resolution to obtain optically enriched final compounds is also discussed.

Keywords: Glucuronidation; Metabolism; PKCε; Phase II; Polarity.

MeSH terms

  • Animals
  • Dogs
  • Dose-Response Relationship, Drug
  • Glucuronides / chemistry
  • Glucuronides / metabolism
  • Glucuronides / pharmacology*
  • Molecular Structure
  • Protein Kinase C-epsilon / antagonists & inhibitors*
  • Protein Kinase C-epsilon / metabolism
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Glucuronides
  • Protein Kinase Inhibitors
  • Protein Kinase C-epsilon