Development of orally active nonpeptidic inhibitors of human neutrophil elastase

Journal of Medicinal Chemistry

Volumn 44, Issue 8, 2001, Pages 1268-1285

  Ohmoto, K ^a   Yamamoto, T ^a   Okuma, M ^a   Horiuchi, T ^a   Imanishi, H ^a   Odagaki, Y ^a   Kawabata, K ^a   Sekioka, T ^a   Hirota, Y ^a   Matsuoka, S ^a   Nakai, H ^a   Toda, M ^a   Cheronis, J C ^b   Spruce, L W ^b   Gyorkos, A ^b   Wieczorek, M ^b  

^a ONO PHARMACEUTICAL CO   (Japan)

^b Departments of New Leads Chemistry and Pharmacology   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (5 AMINO 6 OXO 2 PHENYLHYDROPYRIMIDINYL) N [2 (5 TERT BUTYL 1,3,4 OXADIAZOL 2 YL) 1 (METHYLETHYL) 2 OXOETHYL]ACETAMIDE; 5 AMINO 2 PHENYLPYRIMIDIN 6 ONE DERIVATIVE; ALPHA KETO 1,3,4 OXADIAZOLE DERIVATIVE; HYDROXYL GROUP; LEUKOCYTE ELASTASE; LEUKOCYTE ELASTASE INHIBITOR; N [1 (METHYLETHYL) 2 (5 METHYL 1,3,4 OXADIAZOL 2 YL) 2 OXOETHYL] 2 [5 AMINO 2 (4 FLUOROPHENYL) 6 OXOHYDROPYRIMIDINYL]ACETAMIDE; N [1 (METHYLETHYL) 2 [5 (1 METHYL 1 PHENYLETHYL) 1,3,4 OXADIAZOL 2 YL] 2 OXOETHYL] 2 (5 AMINO 6 OXO 2 PHENYLHYDROPYRIMIDINYL)ACETAMIDE; N [1 (METHYLETHYL) 2 [5 (1 METHYL 1 PHENYLETHYL) 1,3,4 OXADIAZOL 2 YL] 2 OXOETHYL] 2 [2 (4 FLUOROPHENYL) 6 OXOHYDROPYRIMIDINYL]ACETAMIDE; N [1 (METHYLETHYL) 2 [5 [1 METHYL 1 (3 METHYLPHENYL)ETHYL] 1,3,4 OXADIAZOL 2 YL] 2 OXOETHYL] 2 [5 AMINO 2 (4 FLUOROPHENYL) 6 OXOHYDROPYRIMIDINYL]ACETAMIDE; N [1 (METHYLETHYL) 2 OXO 2 (5 BENZYL 1,3,4 OXADIAZOL 2 YL)ETHYL] 2 [5 AMINO 2 (4 FLUOROPHENYL) 6 OXOHYDROPYRIMIDINYL]ACETAMIDE; N [2 (5 BUTYL 1,3,4 OXADIAZOL 2 YL) 1 (METHYLETHYL) 2 OXOETHYL] 2 [5 AMINO 2 (4 FLUOROPHENYL) 6 OXOHYDROPYRIMIDINYL]ACETAMIDE; N [2 (5 TERT BUTYL 1,3,4 OXADIAZOL 2 YL) 1 (METHYLETHYL) 2 OXOETHYL] 2 (5 AMINO 6 OXO 2 PHENYLHYDROPYRIMIDINYL)ACETAMIDE; N [2 (5 TERT BUTYL 1,3,4 OXADIAZOL 2 YL) 1 (METHYLETHYL) 2 OXOETHYL] 2 (6 OXO 2 PHENYLHYDROPYRIMIDINYL)ACETAMIDE; N [2 (5 TERT BUTYL 1,3,4 OXADIAZOL 2 YL) 1 (METHYLETHYL) 2 OXOETHYL] 2 [2 (4 FLUOROPHENYL) 6 OXOHYDROPYRIMIDINYL]ACETAMIDE; N [2 (5 TERT BUTYL 1,3,4 OXADIAZOL 2 YL) 1 (METHYLETHYL) 2 OXOETHYL] 2 [5 AMINO 2 (4 FLUOROPHENYL) 6 OXOHYDROPYRIMIDINYL]ACETAMIDE; N [2 [5 (1 METHYLCYCLOPROPYL) 1,3,4 OXADIAZOL 2 YL] 1 (METHYLETHYL) 2 OXOETHYL] 2 (5 AMINO 6 OXO 2 PHENYLHYDROPYRIMIDINYL)ACETAMIDE; N [2 [5 (1 METHYLCYCLOPROPYL) 1,3,4 OXADIAZOL 2 YL] 1 (METHYLETHYL) 2 OXOETHYL] 2 (6 OXO 2 PHENYLHYDROPYRIMIDINYL)ACETAMIDE; N [2 [5 (1 METHYLCYCLOPROPYL) 1,3,4 OXADIAZOL 2 YL] 1 (METHYLETHYL) 2 OXOETHYL] 2 [2 (4 FLUOROPHENYL) 6 OXOHYDROPYRIMIDINYL]ACETAMIDE; ONO 6818; SERINE; UNCLASSIFIED DRUG;

ARTICLE; ASSAY; BLEEDING; CONTROLLED STUDY; DRUG ACTIVITY; DRUG BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; IN VITRO STUDY; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; CRICETINAE; ENZYME INHIBITORS; HEMORRHAGE; HUMANS; HYDROLYSIS; LEUKOCYTE ELASTASE; LUNG DISEASES; OXADIAZOLES; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0035848574     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm000410y     Document Type: Article

References (29)

1. Neutrophil proteinases
2. Elastases and emphysema. Current assessment of the protease-antiprotease hypothesis
3. Proteinase/proteinase inhibitor imbalance in sputum sol phases from patients with chronic obstructive pulmonary disease. Suggestions for a key role played by antileukoprotease
4. Elastase and α-1-proteinase inhibitor activity in tracheal aspirates during respiratory distress syndrome
5. Interactions of granulocyte proteases with inhibitors in rheumatoid arthritis
6. Elastase in tissue injury
7. Sputum soluble phase proteins and elastase activity in patients with cystic fibrosis
8. Neutrophil-elastase in chronic inflammatory bowel disease: A marker of disease activity?
9. Fecal lactoferrin as a marker for disease activity in inflammatory bowel disease: Comparison with other neutrophil-derived proteins
10. Neutrophil elastase
11. Synthetic inhibitors of elastase
12. Inhibitors of human leukocyte elastase
13. Inhibitors of human neutrophil elastase as a potential treatment for inflammatory diseases
14. Therapeutic promises of leukocyte elastase and macrophage metalloelastase inhibitors for the treatment of pulmonary emphysema
15. Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase
16. Design, synthesis, and kinetic evaluation of a unique class of elastase inhibitors, the peptidyl α-ketobenzoxazoles, and the X-ray crystal structure of the covalent complex between porcine pancreatic elastase and Ac-Ala-Pro-Val-2-benzoxazole
17. Peptidyl α-ketoheterocyclic inhibitors of human neutrophil elastase. 2. Effect of varying the heterocyclic ring on in vitro potency
18. Synthesis of the chiral (8s)-7-Aza-1,3(e),9-decatriene system from natural α-amino acids and its intramolecular diels-alder reaction directed toward chiral trans-hydroisoquinolones
19. Nonpeptidic inhibitors of human leukocyte elastase. 5. Design, synthesis, and X-ray crystallography of a series of orally active 5-aminopyrimidin-6-one-containing trifluoromethyl ketones
20. SC-39026, a specific human neutrophil elastase inhibitor
21. Design of orally active, non-peptidic inhibitors of human leukocyte elastase