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6,6-二甲基吡咯并[3,4-c]吡唑的优化：PHA-793887 的发现，一种强效的 CDK 抑制剂，适合静脉给药。

Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing.

机构信息

Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

出版信息

Bioorg Med Chem. 2010 Mar 1;18(5):1844-53. doi: 10.1016/j.bmc.2010.01.042. Epub 2010 Jan 25.

DOI:10.1016/j.bmc.2010.01.042
PMID:20153204
Abstract

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.

摘要

我们最近报道了基于 6-取代吡咯并[3,4-c]吡嗪核心结构的 CDK 抑制剂。通过提高对多种 CDK 的抑制活性、对癌细胞系的抗增殖活性以及优化物理化学性质，我们鉴定出了高活性化合物。化合物 31（PHA-793887）在人卵巢 A2780、结肠 HCT-116 和胰腺 BX-PC3 癌异种移植模型中显示出良好的疗效，并且通过静脉注射每日治疗时具有良好的耐受性。它被确定为用于临床评估实体瘤患者的候选药物。

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