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

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.

• Authors: K Umekawa, H Hasegawa, Y Tsutsumi, K Sato, Y Matsumura, N Ohashi
• Journal: Japanese journal of pharmacology (Jpn J Pharmacol) Vol. 84 Issue 1 Pg. 7-15 (Sep 2000) ISSN: 0021-5198 [Print] Japan
• PMID: 11043447 (Publication Type: Journal Article)

Chemical References

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

Topics

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