Identification of N,1,4,4-Tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a Potent, Orally Available Cyclin Dependent Kinase Inhibitor

被引：113

作者：

Brasca, Maria Gabriella ^{[1
]}

Amboldi, Nadia ^{[1
]}

Ballinari, Dario ^{[1
]}

Cameron, Alexander ^{[1
]}

Casalc, Elena ^{[1
]}

Cervi, Giovanni ^{[1
]}

Colombo, Maristella ^{[1
]}

Colotta, Francesco ^{[1
]}

Croci, Valter ^{[1
]}

D'Alessio, Roberto ^{[1
]}

Fiorentini, Francesco ^{[2
]}

Isacchi, Antonella ^{[1
]}

Mercurio, Ciro ^{[1
]}

Moretti, Walter ^{[1
]}

Panzeri, Achille ^{[1
]}

Pastori, Wilma ^{[1
]}

Pevarello, Paolo ^{[1
]}

Quartieri, Francesca ^{[1
]}

Roletto, Fulvia ^{[1
]}

Traquandi, Gabriella ^{[1
]}

Vianello, Paola ^{[1
]}

Vulpetti, Anna ^{[1
]}

Ciomei, Marina ^{[1
]}

机构：

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

[2] Accelera Srl, I-20014 Nerviano, MI, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 16期

关键词：

GROWTH-FACTOR RECEPTORS; DISCOVERY;

D O I：

10.1021/jm9006559

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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 synthesize cl, 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 its a drug candidate for further development. Compound 28 is Currently undergoing phase I and phase II clinical trials.

引用

页码：5152 / 5163

页数：12

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