Discovery of a Potent, Selective, and Orally Bioavailable Pyridinyl-Pyrimidine Phthalazine Aurora Kinase Inhibitor

被引：36

作者：

Cee, Victor J. ^{[1
]}

Schenkel, Laurie B. ^{[1
]}

Hodous, Brian L. ^{[1
]}

Deak, Holly L. ^{[1
]}

Nguyen, Hanh N. ^{[1
]}

Olivieri, Philip R. ^{[1
]}

Romero, Karina ^{[1
]}

Bak, Annette ^{[2
]}

Be, Xuhai ^{[3
]}

Bellon, Steve ^{[4
]}

Bush, Tammy L. ^{[5
]}

Cheng, Alan C. ^{[4
]}

Chung, Grace ^{[5
]}

Coats, Steve ^{[5
]}

Eden, Patrick M. ^{[5
]}

Hanestad, Kelly ^{[5
]}

Gallant, Paul L. ^{[6
]}

Gu, Yan ^{[4
]}

Huang, Xin ^{[4
]}

Kendall, Richard L. ^{[5
]}

Lin, Min-Hwa Jasmine ^{[3
]}

Morrison, Michael J. ^{[6
]}

Patel, Vinod F. ^{[1
]}

Radinsky, Robert ^{[5
]}

Rose, Paul E. ^{[4
]}

Ross, Sandra ^{[6
]}

Sun, Ji-Rong ^{[5
]}

Tang, Jin ^{[4
]}

Zhao, Huilin ^{[4
]}

Payton, Marc ^{[5
]}

Geuns-Meyer, Stephanie D. ^{[1
]}

机构：

[1] Amgen Inc, Dept Med Chem, Cambridge, MA 02142 USA

[2] Amgen Inc, Dept Pharmaceut, Cambridge, MA 02142 USA

[3] Amgen Inc, Dept Pharmacokinet & Drug Metab, Cambridge, MA 02142 USA

[4] Amgen Inc, Dept Mol Struct, Cambridge, MA 02142 USA

[5] Amgen Inc, Dept Oncol Res, Cambridge, MA 02142 USA

[6] Amgen Inc, Dept Mol Pharmacol, Cambridge, MA 02142 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 17期

关键词：

ANTICANCER AGENTS; PROTEIN-KINASES; DESIGN; SPINDLE; COMPLEX; DOMAIN; ABL;

D O I：

10.1021/jm100394y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 86 at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.

引用

页码：6368 / 6377

页数：10

共 35 条

[1] Structural basis of Aurora-A activation by TPX2 at the mitotic spindle [J].