取代尿嘧啶衍生物作为聚（ADP - 核糖）聚合酶 -1（PARP - 1）的强效抑制剂。
Substituted uracil derivatives as potent inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1).
作者信息
Steinhagen Henning, Gerisch Michael, Mittendorf Joachim, Schlemmer Karl-Heinz, Albrecht Barbara
机构信息
Institute of Medicinal Chemistry, Pharma Research Centre, Bayer AG, D-42096, Wuppertal, FRG .
出版信息
Bioorg Med Chem Lett. 2002 Nov 4;12(21):3187-90. doi: 10.1016/s0960-894x(02)00602-9.
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.
合成了一类新型的PARP-1抑制剂，即取代稠合尿嘧啶衍生物。从一种IC(50)=2微摩尔的衍生物开始，化学优化程序得到了效力提高100倍以上（IC(50)<20纳摩尔）的化合物。此外，还评估了其物理化学和药代动力学性质。结果表明，带有哌嗪或苯基取代的β丙氨酸-甘氨酸侧链的化合物表现出最佳的整体特性。
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