Nicotinyl aspartyl ketones as inhibitors of caspase-3.
Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact in the treatment of several degenerative diseases. Since P(1) aspartic acid is a required element of recognition for this enzyme, a library of capped aspartyl aldehydes was synthesized using solid-phase chemistry. The 5-bromonicotinamide derivative of the aspartic acid aldehyde was identified to be an inhibitor of caspase-3. Substitution at the 5-position of the pyridine ring and conversion of the aldehyde to ketones led to a series of potent inhibitors of caspase-3.
Isabel
Elise
E
Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada & Co., Pointe-Claire-Dorval, H9R 4P8, Quebec, Canada. elise_isabel@merck.com
Black
W Cameron
WC
Bayly
Christopher I
CI
Grimm
Erich L
EL
Janes
Marc K
MK
McKay
Daniel J
DJ
Nicholson
Donald W
DW
Rasper
Dita M
DM
Renaud
Johanne
J
Roy
Sophie
S
Tam
John
J
Thornberry
Nancy A
NA
Vaillancourt
John P
JP
Xanthoudakis
Steven
S
Zamboni
Robert
R
D000447:Aldehydes / Q000138:chemical synthesis / Q000494:pharmacology; D001224:Aspartic Acid / Q000737:chemistry; D053148:Caspase 3; D061945:Caspase Inhibitors; D002460:Cell Line; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007202:Indicators and Reagents; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology*; D019151:Peptide Library; D011725:Pyridines / Q000737:chemistry
D000447:Aldehydes; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D007659:Ketones; D019151:Peptide Library; D011725:Pyridines; D001224:Aspartic Acid; C505407:CASP3 protein, human; D053148:Caspase 3