Pharmacological characterization of a novel sulfonylureid-pyrazole derivative, SM-19712, a potent nonpeptidic inhibitor of endothelin converting enzyme

Jpn J Pharmacol. 2000 Sep;84(1):7-15. doi: 10.1254/jjp.84.7.

Abstract

We describe the pharmacological characteristics of SM-19712 (4-chloro-N-[[(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]carbonyl] benzenesulfonamide, monosodium salt). SM-19712 inhibited endothelin converting enzyme (ECE) solubilized from rat lung microsomes with an IC50 value of 42 nM and, at 10 - 100 microM, had no effect on other metalloproteases such as neutral endopeptidase 24.11 and angiotensin converting enzyme, showing a high specificity for ECE. In cultured porcine aortic endothelial cells, SM-19712 at 1 - 100 microM concentration-dependently inhibited the endogenous conversion of big endothelin-1 (ET-1) to ET-1 with an IC50 value of 31 microM. In anesthetized rats, either intravenous (1-30 mg/kg) or oral (10-30 mg/kg) administration of SM-19712 dose-dependently suppressed the pressor responses induced by big ET-1. In acute myocardial infarction of rabbits subjected to coronary occlusion and reperfusion, SM-19712 reduced the infarct size, the increase in serum concentration of ET-1 and the serum activity of creatinine phosphokinase. The present study demonstrates that SM-19712 is a structurally novel, nonpeptide, potent and selective inhibitor of ECE, and SM-19712 is a valuable new tool for elucidating the pathophysiological role of ECE.

MeSH terms

  • Acute Disease
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Disease Models, Animal
  • Endothelin-1 / antagonists & inhibitors
  • Endothelin-1 / metabolism
  • Endothelin-Converting Enzymes
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Glycopeptides / pharmacology
  • Lung / enzymology
  • Lung / metabolism
  • Male
  • Metalloendopeptidases
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / prevention & control
  • Pressoreceptors / drug effects
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Substrate Specificity
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use
  • Sulfonylurea Compounds / chemistry
  • Sulfonylurea Compounds / pharmacokinetics
  • Sulfonylurea Compounds / pharmacology*
  • Sulfonylurea Compounds / therapeutic use
  • Swine

Substances

  • Endothelin-1
  • Enzyme Inhibitors
  • Glycopeptides
  • SM 19712
  • Sulfonamides
  • Sulfonylurea Compounds
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • Endothelin-Converting Enzymes
  • phosphoramidon