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

The Japanese Journal of Pharmacology

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

[1] Discovery Research Laboratories I,Research Center,Sumitomo Pharmaceuticals Co.,Ltd.,Osaka 554-0022,Japan;Department of Pharmacology,Osaka University of Pharmaceutical Sciences,Osaka 569-1094,Japan

关键词: Endothelin;    Big endothelin;    Endothelin converting enzyme;    Phosphoramidon;    Acute myocardial infarction;   

DOI  :  10.1254/jjp.84.7

学科分类：药理学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(43)Cited-By(22)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.

【 授权许可】

Unknown