title: 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.affiliation: Discovery Research Laboratories I, Research Center, Sumitomo Pharmaceuticals Co, Ltd, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Umekawa
authors.forename: H
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Y
authors.initials: Y
authors.lastname: Tsutsumi
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumura
authors.forename: N
authors.initials: N
authors.lastname: Ohashi
mesh_terms: D000208:Acute Disease; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006020:Glycopeptides / Q000494:pharmacology; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control; D011311:Pressoreceptors / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013453:Sulfonylurea Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013552:Swine
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D006020:Glycopeptides; C419789:SM 19712; D013449:Sulfonamides; D013453:Sulfonylurea Compounds; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon