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.
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.
Department of Medicinal Chemistry, ZENECA Pharmaceuticals, Wilmington, Delaware 19897.
C A
CA
Veale
J R
JR
Damewood
G B
GB
Steelman
C
C
Bryant
B
B
Gomes
J
J
Williams
D000595:Amino Acid Sequence; D000818:Animals; D002243:Carbolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D006224:Cricetinae; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000494:pharmacology*; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology*; D019272:Leukocyte Elastase; D008969:Molecular Sequence Data; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D002243:Carbolines; D006845:Hydrocarbons, Fluorinated; D007659:Ketones; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase