We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC₅₀ = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC₅₀ = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC₅₀ in the 10−100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.

中文翻译：

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发现2- {4-[（3 S）-哌啶-3-基]苯基} -2 H-吲唑-7-羧酰胺（MK-4827）：一种新型口服聚（ADP-核糖）聚合酶（PARP）抑制剂在BRCA-1和-2突变肿瘤中有效

我们公开了作为聚（ADP-核糖）聚合酶（PARP）1和2抑制剂的新型2-苯基-2 H-吲唑-7-羧酰胺系列的开发。该系列经过优化，可提高酶和细胞活性，所得的PARP抑制剂具有抗BRCA-1和BRCA-2缺陷癌细胞的抗增殖活性，对BRCA熟练的细胞具有较高的选择性。CYP450 1A1和1A2的肝外氧化被认为是新陈代谢的问题，并且据报有改善药代动力学特性的策略。这些努力最终确定了2- {4-[（3 S）-哌啶-3-基]苯基} -2 H-吲唑-7-羧酰胺56（MK-4827）具有良好的药代动力学特性，目前正在进行I期临床试验。该化合物分别对IC ₅₀ = 3.8和2.1 nM表现出优异的PARP 1和2抑制作用，在全细胞试验中，其对EC ₅₀ = 4 nM的PARP活性具有抑制作用，并通过突变的BRCA-1和BRCA抑制癌细胞的增殖。 -2，CC ₅₀在10-100 nM范围内。化合物56在体内具有良好的耐受性，并在BRCA-1缺陷型癌症的异种移植模型中显示出作为单一药物的功效。