Kayo Umekawa1, Hirohiko Hasegawa1, Yasushi Tsutsumi1,
Kimihiko Sato1,
Yasuo Matsumura2 and Naohito Ohashi1,*
1DiscoveryﾊResearch Laboratories I, Research Center, Sumitomo
Pharmaceuticals Co., Ltd., Osaka 554-0022, Japan
2Departmentﾊ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ﾊnM and, at 10-100ﾊ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ﾊmM
concentration-dependently inhibited the endogenous conversion of big endothelin-1
(ET-1) to ET-1 with an IC50 value of 31ﾊmM.
In anesthetized rats, either intravenous (1-30ﾊmg/kg) or oral (10-30ﾊ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ｩ The Japanese Pharmacological Society 2000
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