Substituted uracil derivatives as potent inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

A new class of PARP-1 inhibitors, namely substituted fused uracil derivatives were synthesised. Starting from a derivative with an IC50=2 μM the chemical optimisation program led to compounds with more than a 100-fold increase in potency (IC50<20 nM). Additionally, physicochemical and pharmacokinetic properties were evaluated. It could be shown that compounds bearing a piperazine or phenyl substituted βAla-Gly side chain exhibited the best overall profile.