Non-peptidic inhibitors of human leukocyte elastase. 4. Design, synthesis, and in vitro and in vivo activity of a series of .beta.-carbolinone-containing trifluoromethyl ketones
| Autor: | Chris A. Veale, Gary Steelman, Bruce Gomes, Craig Bryant, James R. Damewood, Joseph Williams |
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| Rok vydání: | 1995 |
| Předmět: |
Ketone
Hydrocarbons Fluorinated Molecular model Stereochemistry Molecular Sequence Data Structure-Activity Relationship chemistry.chemical_compound Cricetinae Drug Discovery Animals Humans Structure–activity relationship Amino Acid Sequence Pancreatic elastase chemistry.chemical_classification Trifluoromethyl Pancreatic Elastase biology Proteolytic enzymes Ketones Enzyme chemistry Biochemistry Enzyme inhibitor biology.protein Molecular Medicine sense organs Leukocyte Elastase Carbolines |
| Zdroj: | Journal of Medicinal Chemistry. 38:86-97 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00001a014 |
| Popis: | A novel series of human leukocyte elastase (HLE) inhibitors containing the beta-carbolinone ring system are reported. The design of these trifluoromethyl ketone-based inhibitors used a combination of structural information obtained from X-ray crystallography and molecular modeling investigations. The beta-carbolinone ring in these compounds serves as a highly efficient peptidiomimetic for the P2-P3 region of peptidyl trifluoromethyl ketone inhibitors of HLE. Several of the beta-carbolinones exhibit significant in vitro potency, with Ki values in the nanomolar range. Using aqueous molecular dynamics simulations, realistic models for the molecular recognition of these inhibitors by HLE have been obtained and are discussed. This series of compounds are found to have excellent selectivity for HLE over a number of other proteolytic enzymes, including closely related enzymes such as porcine pancreatic elastase. |
| Databáze: | OpenAIRE |
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