Rapid optimization of an ICE inhibitor synthesis using multiple reaction conditions in a parallel array.
Optimization of a 2-step reaction sequence was accomplished in 3-4 days, with over 200 different reaction conditions evaluated. Combinatorial arrays were performed using the optimized conditions to synthesize 590 new compounds which were tested for inhibition against N-His (D381E) ICE. Thirty-five compounds showed at least a tenfold improvement in activity compared to an initial standard.
Warmus
J S
JS
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Ryder
T R
TR
Hodges
J C
JC
Kennedy
R M
RM
Brady
K D
KD
D019943:Amino Acid Substitution; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001331:Automation; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D007202:Indicators and Reagents; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007202:Indicators and Reagents; D007659:Ketones; D001224:Aspartic Acid