Lipophilic versus hydrogen-bonding effect in P3 on potency and selectivity of valine aspartyl ketones as caspase 3 inhibitors.
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. The P1 aspartic acid residue is a required element of recognition for this enzyme that was maintained constant along with the adjacent natural valine as the P2 group. The thiobenzylmethylketone warhead on the aspartate was conveniently handled through solid-phase synthesis allowing modification in the P3 region that eventually led to simpler derivatives with increased potency against caspase 3. The key to such an effect is the introduction of hydroxyl group alpha to the P3 carbonyl.
Mellon
Christophe
C
Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada & Co., P.O. Box 1005, Pointe-Claire-Dorval, Que., Canada H9R 4P8. christophe_mellon@merck.com
Aspiotis
Reneé
R
Black
Cameron W
CW
Bayly
Christopher I
CI
Grimm
Erich L
EL
Giroux
André
A
Han
Yongxin
Y
Isabel
Elise
E
McKay
Daniel J
DJ
Nicholson
Donald W
DW
Rasper
Dita M
DM
Roy
Sophie
S
Tam
John
J
Thornberry
Nancy A
NA
Vaillancourt
John P
JP
Xanthoudakis
Steven
S
Zamboni
Robert
R
D001224:Aspartic Acid; D053148:Caspase 3; D061945:Caspase Inhibitors; D020650:Combinatorial Chemistry Techniques; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship; D014633:Valine
D061945:Caspase Inhibitors; D004151:Dipeptides; D004791:Enzyme Inhibitors; D007659:Ketones; D011994:Recombinant Proteins; D001224:Aspartic Acid; C505407:CASP3 protein, human; D053148:Caspase 3; D014633:Valine