Jpn. J. Pharmacol. 84 (1), 7-15 (2000)


Pharmacological Characterization of a Novel Sulfonylureid-Pyrazole Derivative, SM-19712, a Potent Nonpeptidic Inhibitor of Endothelin Converting Enzyme

Kayo Umekawa1, Hirohiko Hasegawa1, Yasushi Tsutsumi1, Kimihiko Sato1,
Yasuo Matsumura2 and Naohito Ohashi1,*

1Discovery Research Laboratories I, Research Center, Sumitomo Pharmaceuticals Co., Ltd., Osaka 554-0022, Japan
2Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan
*To whom correspondence should be addressed.

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 mM, 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 mM concentration-dependently inhibited the endogenous conversion of big endothelin-1 (ET-1) to ET-1 with an IC50 value of 31 mM. 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.

Keywords: Endothelin, Big endothelin, Endothelin converting enzyme, Phosphoramidon, Acute myocardial infarction


Copyright© The Japanese Pharmacological Society 2000

[Back to TOC]