title: Lipophilic versus hydrogen-bonding effect in P3 on potency and selectivity of valine aspartyl ketones as caspase 3 inhibitors.
abstract: 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.
authors: 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
authors: Christophe
authors: C
authors: Mellon
authors: Reneé
authors: R
authors: Aspiotis
authors: Cameron W
authors: CW
authors: Black
authors: Christopher I
authors: CI
authors: Bayly
authors: Erich L
authors: EL
authors: Grimm
authors: André
authors: A
authors: Giroux
authors: Yongxin
authors: Y
authors: Han
authors: Elise
authors: E
authors: Isabel
authors: Daniel J
authors: DJ
authors: McKay
authors: Donald W
authors: DW
authors: Nicholson
authors: Dita M
authors: DM
authors: Rasper
authors: Sophie
authors: S
authors: Roy
authors: John
authors: J
authors: Tam
authors: Nancy A
authors: NA
authors: Thornberry
authors: John P
authors: JP
authors: Vaillancourt
authors: Steven
authors: S
authors: Xanthoudakis
authors: Robert
authors: R
authors: Zamboni
mesh_terms: 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
chemical_list: 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