title: Novel peptidyl alpha-keto amide inhibitors of calpains and other cysteine proteases.
abstract: A series of new dipeptidyl alpha-keto amides of the general structure R1-L-Leu-D,L-AA-CONH-R2 were synthesized and evaluated as inhibitors for the cysteine proteases calpain I, calpain II, and cathepsin B. They combine 10 different N-protecting groups (R1), 3 amino acids residues in P1 (AA), and 44 distinct substituents on the alpha-keto amide nitrogen (R2). In general, calpain II was more sensitive to these inhibitors than calpain I, with a large number of inhibitors displaying dissociation constants (Ki) in the 10-100 nM range. Calpain I was also effectively inhibited, but very low Ki values were observed with a smaller number of inhibitors than with calpain II. Cathepsin B was weakly inhibited by most compounds in this study. The best inhibitors for calpain II were Z-Leu-Abu-CONH-CH2-CHOH-C6H5 (Ki = 15 nM), Z-Leu-Abu-CONH-CH2-2-pyridyl (Ki = 17 nM), and Z-Leu-Abu-CONH-CH2-C6H3(3,5(OMe)2) (Ki = 22 nM). The best calpain I inhibitor in this study was Z-Leu-Nva-CONH-CH2-2-pyridyl (Ki = 19 nM). The peptide alpha-keto amide Z-Leu-Abu-CONH-(CH2)2-3-indolyl was the best inhibitor for cathepsin B (Ki = 31 nM). Some compounds acted as specific calpain inhibitors, with comparable activity on both calpains I and II and a lack of activity on cathepsin B (e.g., 40, 42, 48, 70). Others were specific inhibitors for calpain I (e.g., 73) or calpain II (e.g., 18, 19, 33, 35, 56). Such inhibitors may be useful in elucidating the physiological and pathological events involving these proteases and may become possible therapeutic agents.
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta 30332-0400, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: A C
authors.initials: AC
authors.lastname: Ortega-Vilain
authors.forename: G S
authors.initials: GS
authors.lastname: Patil
authors.forename: D L
authors.initials: DL
authors.lastname: Chu
authors.forename: J E
authors.initials: JE
authors.lastname: Foreman
authors.forename: D D
authors.initials: DD
authors.lastname: Eveleth
authors.forename: J C
authors.initials: JC
authors.lastname: Powers
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000648:ultrastructure; D002154:Calpain / Q000037:antagonists & inhibitors*; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D002463:Cell Membrane Permeability; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D002154:Calpain; D002401:Cathepsin B