Pharmacological activities of TEI-8362, a novel inhibitor of human neutrophil elastase.
1. TEI-8362, 4-(N-(3-((3-carboxypropyl)amino)-8-methyl-1-oxo-4-azaisochromen-6- yl)carbamoyl)-4-((phenylmethoxy)carbonylamino)butanoic acid (C26H28N4O9) is a novel inhibitor of human neutrophil elastase (HNE). We evaluated its pharmacological profile in vitro and in vivo. 2. TEI-8362 demonstrated potent inhibition of HNE with a Ki value of 1.38 x 10(-9) M. Its selectivity for HNE among a variety of proteases ranged from 163 fold to 68,000 fold in favour of HNE. 3. The pulmonary haemorrhage that occurred after i.t. instillation of HNE to hamsters was inhibited by either i.t., i.v., or inhalant administration of TEI-8362. 4. Intratracheal administration of lipopolysaccharide induced pulmonary neutrophilia. Twenty-four hours after lipopolysaccharide administration, the additional treatment with formyl-methionyl-leucyl-phenylalanine resulted in a specific neutrophil-dependent acute lung injury. In this model, lung injury was significantly attenuated by i.t., i.v., or inhalant administration of TEI-8362. 5. These pharmacological actions of TEI-8362 suggest that this drug has therapeutic value in the treatment of destructive lung diseases due to neutrophils.
Mitsuhashi
H
H
Teijin Institute for Bio-Medical Research, Hino, Tokyo, Japan. h.mitsuhashi@teijin.co.jp
Nonaka
T
T
Hamamura
I
I
Kishimoto
T
T
Muratani
E
E
Fujii
K
K
D000818:Animals; D002087:Butyrates; D020148:Butyric Acid / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology*; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008647:Mesocricetus; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D013379:Substrate Specificity
D002087:Butyrates; D002219:Carbamates; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D020011:Protective Agents; C119150:TEI 8362; D020148:Butyric Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019272:Leukocyte Elastase