New fatty acid oxidation inhibitors with increased potency lacking adverse metabolic and electrophysiological properties

Bioorg Med Chem Lett. 2004 Jan 19;14(2):549-52. doi: 10.1016/j.bmcl.2003.09.093.

Abstract

New inhibitors of palmitoylCoA oxidation were synthesized based on a structurally novel lead, CVT-3501 (1). Investigation of structure-activity relationships was conducted with respect to potency of inhibition of cardiac mitochondrial palmitoylCoA oxidation and metabolic stability. Potent and metabolically stable analogues 33, 42, and 43 were evaluated in vitro for cytochrome P450 inhibition and potentially adverse electrophysiological effects. Compound 33 was also found to have favorable pharmacokinetic properties in rat.

Publication types

  • Comparative Study

MeSH terms

  • 3-Hydroxyacyl CoA Dehydrogenases / antagonists & inhibitors*
  • 3-Hydroxyacyl CoA Dehydrogenases / metabolism*
  • Acetyl-CoA C-Acyltransferase / antagonists & inhibitors*
  • Acetyl-CoA C-Acyltransferase / metabolism*
  • Animals
  • Carbon-Carbon Double Bond Isomerases / antagonists & inhibitors*
  • Carbon-Carbon Double Bond Isomerases / metabolism*
  • Drug Stability
  • Electrophysiology
  • Enoyl-CoA Hydratase / antagonists & inhibitors*
  • Enoyl-CoA Hydratase / metabolism*
  • Enzyme Inhibitors / adverse effects*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Guinea Pigs
  • In Vitro Techniques
  • Racemases and Epimerases / antagonists & inhibitors*
  • Racemases and Epimerases / metabolism*
  • Rats

Substances

  • Enzyme Inhibitors
  • fatty acid oxidation complex
  • 3-Hydroxyacyl CoA Dehydrogenases
  • Acetyl-CoA C-Acyltransferase
  • Enoyl-CoA Hydratase
  • Racemases and Epimerases
  • Carbon-Carbon Double Bond Isomerases