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

We describe the pharmacological characteristics of SM-19712 (4-chloro-N-[[( 4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)amino] carbonyl]benzenesulfonamid e, 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 mu M, had no effect on other metalloproteases such as neutral endope ptidase 24.11 and angiotensin converting enzyme, showing a high specificity for ECE. In cultured porcine aortic endothelial cells, SM-19712 at 1 - 100 mu M concentration-dependently inhibited the endogenous conversion of big endothelin-1 (ET-1) to ET-1 with an IC50 value of 31 mu M. In anesthetized rats, either intravenous (1 - 30 mg/kg) or oral (10 - 30 mg/kg) administrat ion of SM-19712 dose-dependently suppressed the presser responses induced b y 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-I and the serum activity of creatinine phosph okinase. The present study demonstrates that SM-19712 is a structurally nov el, nonpeptide, potent and selective inhibitor of ECE, and SM-19712 is a va luable new tool for elucidating the pathophysiological role of ECE.