Discovery of novel aspartyl ketone dipeptides as potent and selective caspase-3 inhibitors.
The discovery of a series of potent, selective and reversible dipeptidyl caspase-3 inhibitors are reported. The iterative discovery process of using combinatorial chemistry, parallel synthesis, moleculare modelling and structural biology will be discussed.
Han
Yongxin
Y
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada & Co, PO Box 1005, Pointe-Claire-Dorval, Québec, Canada H9R 4P8. yongxin_han@merck.com
Giroux
André
A
Grimm
Erich L
EL
Aspiotis
Renée
R
Francoeur
Sébastien
S
Bayly
Christopher I
CI
Mckay
Daniel J
DJ
Roy
Sophie
S
Xanthoudakis
Steve
S
Vaillancourt
John P
JP
Rasper
Dita M
DM
Tam
John
J
Tawa
Paul
P
Thornberry
Nancy A
NA
Paterson
Erin P
EP
Garcia-Calvo
Margarita
M
Becker
Joseph W
JW
Rotonda
Jennifer
J
Nicholson
Donald W
DW
Zamboni
Robert J
RJ
D001224:Aspartic Acid / Q000737:chemistry*; D001665:Binding Sites; D053148:Caspase 3; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000494:pharmacology; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D061945:Caspase Inhibitors; D004151:Dipeptides; D004791:Enzyme Inhibitors; D007659:Ketones; D001224:Aspartic Acid; C505407:CASP3 protein, human; D053148:Caspase 3