Document Detail

Peptide alpha-keto ester, alpha-keto amide, and alpha-keto acid inhibitors of calpains and other cysteine proteases.
MedLine Citation:
PMID:  8230139     Owner:  NLM     Status:  MEDLINE    
A series of dipeptidyl and tripeptidyl alpha-keto esters, alpha-keto amides, and alpha-keto acids having leucine in the P2 position were synthesized and evaluated as inhibitors for the cysteine proteases calpain I, calpain II, cathepsin B, and papain. In general, peptidyl alpha-keto acids were more inhibitory toward calpain I and II than alpha-keto amides, which in turn were more effective than alpha-keto esters. In the series Z-Leu-AA-COOEt, the inhibitory potency decreased in the order: Met (lowest KI) > Nva > Phe > 4-Cl-Phe > Abu > Nle (highest KI) with calpain I, while almost the reverse order was observed for calpain II. Extending the dipeptide alpha-keto ester to a tripeptide alpha-keto ester yielded significant enhancement in the inhibitory potency toward cathepsin B, but smaller changes toward the calpains. Changing the ester group in the alpha-keto esters did not substantially decrease KI values for calpain I and calpain II. N-Monosubstituted alpha-keto amides were better inhibitors than the corresponding alpha-keto esters. alpha-Keto amides with hydrophobic alkyl groups or alkyl groups with an attached phenyl group had the lower KI values. N,N-Disubstituted alpha-keto amides were much less potent inhibitors than the corresponding N-monosubstituted peptide alpha-keto amides. The peptide alpha-keto acid Z-Leu-Phe-COOH was the best inhibitor for calpain I (KI = 0.0085 microM) and calpain II (KI = 0.0057 microM) discovered in this study. It is likely that the inhibitors are transition-state analogs and form tetrahedral adducts with the active site cysteine of cysteine proteases and form hydrogen bonds with the active site histidine and possibly another hydrogen bond donor in the case of monosubstituted amides. Several inhibitors prevented spectrin degradation in a platelet membrane permeability assay and may be useful for the treatment of diseases which involve neurodegeneration.
Z Li; G S Patil; Z E Golubski; H Hori; K Tehrani; J E Foreman; D D Eveleth; R T Bartus; J C Powers
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  36     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1993 Oct 
Date Detail:
Created Date:  1993-12-10     Completed Date:  1993-12-10     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  3472-80     Citation Subset:  IM    
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta 30332-0400.
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MeSH Terms
Amides / chemical synthesis,  pharmacology
Amino Acid Sequence
Blood Platelets / drug effects,  metabolism
Calpain / antagonists & inhibitors*,  pharmacology*
Cell Membrane Permeability / drug effects
Cysteine Proteinase Inhibitors / blood,  chemical synthesis*,  pharmacology*
Dipeptides / blood,  chemical synthesis,  pharmacology
Esters / chemical synthesis,  pharmacology
Keto Acids / chemical synthesis,  pharmacology
Molecular Sequence Data
Peptides / blood,  chemical synthesis*,  pharmacology*
Structure-Activity Relationship
Substrate Specificity
Reg. No./Substance:
0/Amides; 0/Cysteine Proteinase Inhibitors; 0/Dipeptides; 0/Esters; 0/Keto Acids; 0/Peptides; EC 3.4.22.-/Calpain

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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