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.