Peptidyl alpha-ketoamides with nucleobases, methylpiperazine, and dimethylaminoalkyl substituents as calpain inhibitors.
A series of peptidyl alpha-ketoamides with the general structure Cbz-L-Leu-D,L-AA-CONH-R were synthesized and evaluated as inhibitors for the cysteine proteases calpain I, calpain II, and cathepsin B. Nucleobases, methylpiperazine, and dimethylaminoalkyl groups were incorporated into the primed region of the inhibitors to generate compounds that potentially cross the blood-brain barrier. Two of these compounds (Cbz-Leu-D,L-Abu-CONH-(CH(2))(3)-adenin-9-yl and Cbz-Leu-D,L-Abu-CONH-(CH(2))(3)-(4-methylpiperazin-1-yl) have been shown to have useful concentrations in the brain in animals. The best inhibitor for calpain I was Cbz-Leu-D,L-Abu-CONH-(CH(2))(3)-2-methoxyadenin-9-yl (K(i) = 23 nM), and the best inhibitor for calpain II was Cbz-Leu-D,L-Phe-CONH-(CH(2))(3)-adenin-9-yl (K(i) = 68 nM). On the basis of the crystal structure obtained with heterocyclic peptidyl alpha-ketoamides, we have improved inhibitor potency by introducing a small hydrophobic group on the adenine ring. These inhibitors have good potential to be used in the treatment of neurodegenerative diseases.
Ovat
Asli
A
School of Chemistry and Biochemistry, Georgia Institute of Technology, 901 Atlantic Drive, Atlanta, Georgia 30332, USA.
Li
Zhao Zhao
ZZ
Hampton
Christina Y
CY
Asress
Seneshaw A
SA
Fernández
Facundo M
FM
Glass
Jonathan D
JD
Powers
James C
JC
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013552:Swine; D014018:Tissue Distribution
C552331:3-(benzyloxycarbonylleucylamino)-N-(3-(4-methylpiperazin-1-yl)propyl)-2-oxopentanamide; C552332:3-(benzyloxycarbonylleucylamino)-N-(3-(6-amino-9H-purin-9-yl)propyl)-2-oxopentanamide; D004151:Dipeptides; D010879:Piperazines; D002154:Calpain; D002401:Cathepsin B; D000225:Adenine