The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine−threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials.

中文翻译：

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的识别Ñ，1,4,4-四甲基-8 - {[4-（4-甲基哌嗪-1-基）苯基]氨基} -4,5-二氢- 1 H ^ -吡唑并[4,3- ħ ]喹唑啉-3-羧酰胺（PHA-848125），一种有效的，口服可用的细胞周期蛋白依赖性激酶抑制剂

描述了新型的细胞周期蛋白依赖性激酶（CDKs）抑制剂的发现。从化合物1开始，它显示出作为CDKs抑制剂的良好效能，但对一组丝氨酸-苏氨酸和酪氨酸激酶的选择性较差，因此合成了新的类似物。选择性的增强，针对A2780人卵巢癌细胞的抗增殖活性以及物理性质和药代动力学特性的优化导致鉴定出高效和口服有效的化合物。化合物28（PHA-848125）在临床前异种移植A2780人卵巢癌模型中显示出良好的疗效，并且在每天重复治疗后具有良好的耐受性，已被确定为进一步开发的候选药物。化合物28 目前正在进行I期和II期临床试验。