Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing
Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing
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DOI：
10.1016/j.bmc.2010.01.042
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发表时间：
2010-03-01
影响因子：
3.5
通讯作者：
Ciomei, Marina
中科院分区：
文献类型：
--
作者：
Brasca, Maria Gabriella;Albanese, Clara;Ciomei, Marina
我们最近报道了基于6-取代的吡咯并[3，4-c]吡唑核心结构的CDK抑制剂。对多种CDK的抑制效力的提高、对癌细胞系的抗增殖活性和物理化学性质的优化导致了高效化合物的鉴定。化合物31（PHA-793887）在人卵巢A2780、结肠HCT-116和胰腺BX-PC 3癌异种移植物模型中显示出良好的功效，并且在通过静脉内给药每日治疗后耐受良好。它被确定为实体瘤患者临床评价的候选药物。(C)2010爱思唯尔有限公司版权所有。
We have recently reported CDK inhibitors based on the 6-substituted pyrrolo[3,4-c]pyrazole core structure. Improvement of inhibitory potency against multiple CDKs, antiproliferative activity against cancer cell lines and optimization of the physico-chemical properties led to the identification of highly potent compounds. Compound 31 (PHA-793887) showed good efficacy in the human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma xenograft models and was well tolerated upon daily treatments by iv administration. It was identified as a drug candidate for clinical evaluation in patients with solid tumors. (C) 2010 Elsevier Ltd. All rights reserved.