A series of 1-H-pyrazole-3-carboxamide derivatives have been designed and synthesized that exhibit excellent FLT3 and CDK inhibition and antiproliferative activities. A structure–activity-relationship study illustrates that the incorporation of a pyrimidine-fused heterocycle at position 4 of the pyrazole is critical for FLT3 and CDK inhibition. Compound 50 (FN-1501), which possesses potent inhibitory activities against FLT3, CDK2, CDK4, and CDK6 with IC₅₀ values in the nanomolar range, shows antiproliferative activities against MV4-11 cells (IC₅₀: 0.008 μM), which correlates with the suppression of retinoblastoma phosphorylation, FLT3, ERK, AKT, and STAT5 and the onset of apoptosis. Acute-toxicity studies in mice show that compound 50 (LD₅₀: 186 mg/kg) is safer than AT7519 (32 mg/kg). In MV4-11 xenografts in a nude-mouse model, compound 50 can induce tumor regression at the dose of 15 mg/kg, which is more efficient than cytarabine (50 mg/kg). Taken together, these results demonstrate the potential of this unique compound for further development into a drug applied in acute-myeloid-leukemia (AML) therapeutics.

中文翻译：

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4-（（7 H-吡咯并[2,3- d ]嘧啶-4-基）氨基）-N-（4-（（4-甲基哌嗪-1-基）甲基）苯基）-1 H-吡唑的发现-3-羧酰胺（FN-1501），一种FLT3-和CDK激酶抑制剂，对急性粒细胞白血病具有潜在的高效率

已经设计并合成了一系列具有优异的FLT3和CDK抑制作用和抗增殖活性的1- H-吡唑-3-甲酰胺衍生物。结构-活性-关系研究表明，在吡唑的4位掺入嘧啶融合的杂环对于FLT3和CDK抑制至关重要。化合物50（FN-1501）具有对FLT3，CDK2，CDK4和CDK6的有效抑制活性，IC ₅₀值在纳摩尔范围内，显示出对MV4-11细胞的抗增殖活性（IC ₅₀：0.008μM），与抑制视网膜母细胞瘤的磷酸化，FLT3，ERK，AKT和STAT5以及凋亡的发生。小鼠的急性毒性研究表明该化合物50（LD ₅₀：186 mg / kg）比AT7519（32 mg / kg）更安全。在裸鼠模型的MV4-11异种移植物中，化合物50可以以15 mg / kg的剂量诱导肿瘤消退，这比阿糖胞苷（50 mg / kg）更有效。综上所述，这些结果证明了这种独特化合物在进一步发展为用于急性髓细胞白血病（AML）治疗剂的药物中的潜力。