Uejima Y, Kokubo M, Oshida J, Kawabata H, Kato Y, Fujii K
Division of Biochemistry, Teijin Institute for Biomedical Research, Tokyo, Japan.
J Pharmacol Exp Ther. 1993 May;265(2):516-23.
Inhibitors of human leukocyte elastase (HLE) may exert potent therapeutic effects on pulmonary emphysema, adult respiratory distress syndrome and other diseases involving tissue degradation. 7-(4-Chlorophenylsulfonyl-L-glutanyl)amino-5-methyl-2-isopro pylamino-4H-3,1- benzoxazin-4-one (TEI-5624) and 7-(4-chlorophenylsulfonyl-L-lysyl)amino-5-methyl-2- isopropylamino-4H-3,1-benzoxazin-4-one (TEI-6344), two derivatives of 5-methyl-4H-3,1-benzoxazin-4-one, showed strong and highly specific inhibition of human sputum elastase (HSE), which is equivalent to HLE, with Ki values of 6.91 and 16.3 nM, respectively. The selectivity of TEI-5624 for HSE vs. several proteinases ranged from 300-fold to 45,000-fold in favor of HSE. TEI-5624 and TEI-6344 also efficiently prevented degradation of insoluble elastin by stimulated polymorphonuclear leukocytes. The elastase inhibitory capacity of these compounds was not affected by treatment with stimulated polymorphonuclear leukocytes or Pseudomonas aeruginosa-origin elastase. When administered intratracheally to hamsters. TEI-5624 and TEI-6344 were eliminated from the lung with half-times of 85 and 240 min, respectively. In acute injury induced by intratracheal administration of HSE in hamsters, these compounds significantly suppressed pulmonary hemorrhage when administered intratracheally (1 mg/kg) either 30 or 240 min before challenge with HSE (1 mg/kg). HSE-induced emphysema in hamsters was also prevented by TEI-5624 (1 mg/kg) administered intratracheally 7 hr after HSE administration (1 mg/kg). These results suggest that TEI-5624 and TEI-6344 may be useful therapeutic agents for the treatment of HLE-mediated diseases.
人白细胞弹性蛋白酶（HLE）抑制剂可能对肺气肿、成人呼吸窘迫综合征及其他涉及组织降解的疾病发挥强大的治疗作用。7-（4-氯苯基磺酰基-L-谷氨酰基）氨基-5-甲基-2-异丙氨基-4H-3,1-苯并恶嗪-4-酮（TEI-5624）和7-（4-氯苯基磺酰基-L-赖氨酰基）氨基-5-甲基-2-异丙氨基-4H-3,1-苯并恶嗪-4-酮（TEI-6344），5-甲基-4H-3,1-苯并恶嗪-4-酮的两种衍生物，对人痰液弹性蛋白酶（HSE）表现出强烈且高度特异性的抑制作用，HSE等同于HLE，其Ki值分别为6.91和16.3 nM。TEI-5624对HSE相对于几种蛋白酶的选择性在300倍至45000倍之间，有利于HSE。TEI-5624和TEI-6344还能有效防止受刺激的多形核白细胞对不溶性弹性蛋白的降解。这些化合物的弹性蛋白酶抑制能力不受受刺激的多形核白细胞或铜绿假单胞菌来源的弹性蛋白酶处理的影响。当经气管内给予仓鼠时，TEI-5624和TEI-6344从肺中消除的半衰期分别为85和240分钟。在仓鼠经气管内给予HSE诱导的急性损伤中，这些化合物在HSE（1 mg/kg）攻击前30或240分钟经气管内给予（1 mg/kg）时，能显著抑制肺出血。HSE给药（1 mg/kg）7小时后经气管内给予TEI-5624（1 mg/kg）也可预防仓鼠中HSE诱导的肺气肿。这些结果表明，TEI-5624和TEI-6344可能是治疗HLE介导疾病的有用治疗剂。
