Rapid optimization of an ICE inhibitor synthesis using multiple reaction conditions in a parallel array

Bioorg Med Chem Lett. 1998 Sep 8;8(17):2309-14. doi: 10.1016/s0960-894x(98)00418-1.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Substitution
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / chemical synthesis*
  • Aspartic Acid / chemistry
  • Aspartic Acid / pharmacology
  • Automation
  • Caspase Inhibitors*
  • Cysteine Proteinase Inhibitors / chemical synthesis*
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology
  • Drug Design
  • Indicators and Reagents
  • Ketones / chemical synthesis*
  • Ketones / chemistry
  • Ketones / pharmacology
  • Kinetics
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Indicators and Reagents
  • Ketones
  • Aspartic Acid