取代的 2-苯基-2H-吲唑-7-甲酰胺的合成及生物评价作为有效的多聚（ADP-核糖）聚合酶（PARP）抑制剂。
Synthesis and biological evaluation of substituted 2-phenyl-2H-indazole-7-carboxamides as potent poly(ADP-ribose) polymerase (PARP) inhibitors.
机构信息
IRBM-Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia 00040, Rome, Italy.
出版信息
Bioorg Med Chem Lett. 2010 Jan 15;20(2):488-92. doi: 10.1016/j.bmcl.2009.11.127. Epub 2009 Dec 1.
A potent series of substituted 2-phenyl-2H-indazole-7-carboxamides were synthesized and evaluated as inhibitors of poly (ADP-ribose) polymerase (PARP). This extensive SAR exploration culminated with the identification of substituted 5-fluoro-2-phenyl-2H-indazole-7-carboxamide analog 48 which displayed excellent PARP enzyme inhibition with IC(50)=4nM, inhibited proliferation of cancer cell lines deficient in BRCA-1 with CC(50)=42nM and showed encouraging pharmacokinetic properties in rats compared to the lead 6.
我们合成了一系列强效取代的 2-苯基-2H-吲唑-7-甲酰胺，并将其评估为多聚（ADP-核糖）聚合酶（PARP）的抑制剂。通过广泛的 SAR 研究，最终确定了取代的 5-氟-2-苯基-2H-吲唑-7-甲酰胺类似物 48，其对 PARP 酶的抑制作用具有优异的 IC50=4nM，对缺乏 BRCA-1 的癌细胞系的增殖抑制作用具有优异的 CC50=42nM，并且与先导化合物 6 相比，在大鼠中具有令人鼓舞的药代动力学特性。
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