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

The effects of changes in substitution in a series of 5-amino-2-pyrimidin-6-ones on both in vitro activity and oral activity in an acute hemorrhagic assay have been explored. These compounds contained either a trifluoromethyl ketone or a boronic acid moiety to bind covalently to the Ser-195 hydroxyl...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-01, Vol.38 (1), p.98-108
Main Authors: Veale, Chris A, Bernstein, Peter R, Bryant, Craig, Ceccarelli, Christopher, Damewood, James R. Jr, Earley, Roger, Feeney, Scott W, Gomes, Bruce, Kosmider, Ben J
Format: Article
Language:English
Subjects:
Administration, Oral
Amino Acid Sequence
Animals
Biological Availability
Cricetinae
Crystallography, X-Ray
Dogs
Humans
Hydrocarbons, Fluorinated - chemical synthesis
Hydrocarbons, Fluorinated - chemistry
Hydrocarbons, Fluorinated - pharmacology
Ketones - chemical synthesis
Ketones - chemistry
Ketones - pharmacology
Leukocyte Elastase
Models, Biological
Molecular Sequence Data
Molecular Structure
Pancreatic Elastase - antagonists & inhibitors
Pancreatic Elastase - chemistry
Pancreatic Elastase - metabolism
Protein Conformation
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Rats
Structure-Activity Relationship
Swine
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Summary:The effects of changes in substitution in a series of 5-amino-2-pyrimidin-6-ones on both in vitro activity and oral activity in an acute hemorrhagic assay have been explored. These compounds contained either a trifluoromethyl ketone or a boronic acid moiety to bind covalently to the Ser-195 hydroxyl of human leukocyte elastase (HLE). Boronic acid-containing inhibitors were found to be more potent than the corresponding trifluoromethyl ketones in vitro but were less active upon oral administration. Compound 13b was found to offer the best combination of oral potency, duration of action, and enzyme selectivity and, as such, was selected for further biological testing. X-ray crystallography of a cocrystallized complex of compound 19m and porcine pancreatic elastase demonstrated that the inhibitor is bound to the enzyme in a manner similar to that found previously for a closely related series of pyridone-containing inhibitors of HLE.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00001a015