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Potent selective nonpeptidic inhibitors of human lung tryptase.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 1999 Jul 20; Vol. 96 (15), pp. 8348-52. - Publication Year :
- 1999
-
Abstract
- Human lung tryptase, a homotetrameric serine protease unique to mast cell secretory granules, has been implicated in the pathogenesis of asthma. A hypothesis that tethered symmetrical inhibitors might bridge two adjacent active sites was explored via a rationally designed series of bisbenzamidines. These compounds demonstrated a remarkable distanced-defined structure-activity relationship against human tryptase with one series possessing subnanomolar potencies. Additional evidence supporting the concept of active-site bridging is also presented.
- Subjects :
- Asthma etiology
Benzamidines chemical synthesis
Benzamidines pharmacology
Binding Sites
Chymases
Enzyme Inhibitors chemical synthesis
Humans
Kinetics
Mast Cells enzymology
Molecular Structure
Protein Conformation
Structure-Activity Relationship
Substrate Specificity
Tryptases
Enzyme Inhibitors pharmacology
Lung enzymology
Serine Endopeptidases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 96
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 10411878
- Full Text :
- https://doi.org/10.1073/pnas.96.15.8348