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Title
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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.
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Authors
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C.A.Veale,
J.R.Damewood,
G.B.Steelman,
C.Bryant,
B.Gomes,
J.Williams.
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Ref.
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J Med Chem, 1995,
38,
86-97.
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PubMed id
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Abstract
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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.
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