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 IC(50)=2microM the chemical optimisation program led to compounds with more than a 100-fold increase in potency (IC(50)<20nM). Additionally, physicochemical and pharmacokinetic properties were evaluated. It could be shown that compounds bearing a piperazine or phenyl substituted betaAla-Gly side chain exhibited the best overall profile.
Steinhagen
Henning
H
Institute of Medicinal Chemistry, Pharma Research Centre, Bayer AG, D-42096, Wuppertal, FRG . henning.steinhagen@aventis.com
Gerisch
Michael
M
Mittendorf
Joachim
J
Schlemmer
Karl-Heinz
KH
Albrecht
Barbara
B
D000818:Animals; D019540:Area Under Curve; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011994:Recombinant Proteins; D014498:Uracil