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

被引：55

作者：

Brasca, Maria Gabriella ^{[1
]}

Albanese, Clara ^{[1
]}

Alzani, Rachele ^{[1
]}

Amici, Raffaella ^{[2
]}

Avanzi, Nilla ^{[1
]}

Ballinari, Dario ^{[1
]}

Bischoff, James

Borghi, Daniela ^{[1
]}

Casale, Elena ^{[1
]}

Croci, Valter ^{[1
]}

Fiorentini, Francesco ^{[3
]}

Isacchi, Antonella ^{[1
]}

Mercurio, Ciro ^{[2
]}

Nesi, Marcella ^{[1
]}

Orsini, Paolo ^{[1
]}

Pastori, Wilma ^{[1
]}

Pesenti, Enrico ^{[1
]}

Pevarello, Paolo ^{[4
]}

Roussel, Patrick

Varasi, Mario ^{[2
]}

Volpi, Daniele ^{[1
]}

Vulpetti, Anna

Ciomei, Marina ^{[1
]}

机构：

[1] Nerviano Med Sci Srl, Business Unit Oncol, I-20014 Nerviano, MI, Italy

[2] Congenia Srl, Milan, Italy

[3] Accelera, I-20014 Nerviano, MI, Italy

[4] Newron, Milan, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 05期

关键词：

Kinase; Cyclin dependent kinases; CDK; Kinase inhibitor; Tumor cell proliferation inhibition; Cell cycle; Anti-cancer; CYCLIN-DEPENDENT KINASE; CELL-CYCLE; DISCOVERY;

D O I：

10.1016/j.bmc.2010.01.042

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1844 / 1853

页数：10

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