Analogs of a potent maxi-K potassium channel opener with an improved inhibitory profile toward cytochrome P450 isozymes

Bioorg Med Chem Lett. 2005 Oct 1;15(19):4286-90. doi: 10.1016/j.bmcl.2005.06.056.

Abstract

Quinolinone 1 is a potent maxi-K potassium channel opener. In an effort to design analogs of 1 with a better inhibitory profile toward the CYP2C9 isozyme, the two acidic sites were chemically modified independently to generate a number of analogs. These analogs were evaluated as maxi-K channel openers in vitro using Xenopus laevis oocytes expressing cloned hSlo maxi-K channels. Compounds 15, 17, and 19 showed potent activity as maxi-K channel openers and were further evaluated for inhibition of the activity of the CYP2C9 isozyme. Compounds 17 and 19 showed diminished inhibitory potency against 2C9 and also against a panel of other more common CYP isozymes.

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
  • Binding Sites
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 Enzyme Inhibitors
  • Humans
  • Inhibitory Concentration 50
  • Isoenzymes / antagonists & inhibitors
  • Oocytes
  • Quinolones / chemical synthesis*
  • Quinolones / pharmacology
  • Structure-Activity Relationship
  • Xenopus laevis

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Isoenzymes
  • Quinolones
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases