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

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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 10−100μM, 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 1−100μM concentration−dependently inhibited the endogenous conversion of big endothelin−1(ET−1)to ET−1 with an IC50 value of 31μM.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.
社団法人日本薬理学会の論文
2000-09-01