Alpha,beta-unsaturated N-acylpyrrole peptidyl derivatives: new proteasome inhibitors.

Because of the encouraging results obtained using vinyl ester derivatives, we synthesized and tested a novel series of peptide-based proteasome inhibitors bearing a new pharmacophore unit at the C-terminal. N-Acylpyrrole moiety is a potential substrate for Michael addition by catalytic threonine. Several analogues have demonstrated a selective inhibition of the multicatalytic complex beta1 subunits, the capacity to permeate cellular membrane, and good pharmacokinetics properties.