Orally Active Trifluoromethyl Ketone Inhibitors of Human Leukocyte Elastase

This paper describes the development a series of peptidyl trifluoromethyl ketone inhibitors of human leukocyte elastase which are found to have excellent pharmacological profiles. Methods have been developed that allow for the synthesis of these inhibitors in stereochemically pure form. Two of these...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 1997-09, Vol.40 (20), p.3173-3181
Main Authors: Veale, Chris A, Bernstein, Peter R, Bohnert, Claudia M, Brown, Frederick J, Bryant, Craig, Damewood, James R, Earley, Roger, Feeney, Scott W, Edwards, Philip D, Gomes, Bruce, Hulsizer, James M, Kosmider, Ben J, Krell, Robert D, Moore, Gary, Salcedo, Theodora W, Shaw, Andrew, Silberstein, David S, Steelman, Gary B, Stein, Mark, Strimpler, Anne, Thomas, Roy M, Vacek, Edward P, Williams, Joseph C, Wolanin, Donald J, Woolson, Sheila
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biological and medical sciences
Biological Availability
Cricetinae
Dogs
Humans
Isomerism
Leukocyte Elastase - antagonists & inhibitors
Medical sciences
Oligopeptides - administration & dosage
Oligopeptides - chemical synthesis
Oligopeptides - chemistry
Oligopeptides - pharmacokinetics
Oligopeptides - pharmacology
Pharmacology. Drug treatments
Rats
Respiratory system
Serine Proteinase Inhibitors - administration & dosage
Serine Proteinase Inhibitors - chemical synthesis
Serine Proteinase Inhibitors - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:This paper describes the development a series of peptidyl trifluoromethyl ketone inhibitors of human leukocyte elastase which are found to have excellent pharmacological profiles. Methods have been developed that allow for the synthesis of these inhibitors in stereochemically pure form. Two of these compounds, 1k and 1l, have high levels of oral bioavailability in several species. Compound 1l has entered development as ZD8321 and is presently undergoing clinical evaluation. These compounds demonstrate that peptidyl trifluoromethyl ketone inhibitors can achieve high levels of oral activity and bioavailability, and therefore they may prove useful as therapeutic agents in the treatment of diseases in which elastase is implicated.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm970250z