Synthesis and SAR of 1-acetanilide-4-aminopyrazole-substituted quinazolines: Selective inhibitors of Aurora B kinase with potent anti-tumor activity

被引：41

作者：

Foote, Kevin M. ^{[1
]}

Mortlock, Andrew A. ^{[1
]}

Heron, Nicola M. ^{[1
]}

Jung, Frederic H. ^{[2
]}

Hill, George B. ^{[1
]}

Pasquet, Georges ^{[2
]}

Brady, Madeleine C. ^{[1
]}

Green, Stephen ^{[1
]}

Heaton, Simon P. ^{[1
]}

Kearney, Sarah ^{[1
]}

Keen, Nicholas J. ^{[1
]}

Odedra, Rajesh ^{[1
]}

Wedge, Stephen R. ^{[1
]}

Wilkinson, Robert W. ^{[1
]}

机构：

[1] AstraZeneca, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England

[2] AstraZeneca, Ctr Rech, F-51689 Reims 2, France

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 06期

关键词：

Aurora; kinase; quinazoline; pyrazole;

D O I：

10.1016/j.bmcl.2008.02.002

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new class of 1-acetanilide-4-aminopyrazole-substituted quinazoline Aurora kinase inhibitors has been discovered possessing highly potent cellular activity. Continuous infusion into athymic mice bearing SW620 tumors of the soluble phosphate derivative 2 led to dose-proportional exposure of the des-phosphate compound 8 with a high-unbound fraction. The combination of potent cell activity and high free-drug exposure led to pharmacodynamic changes in the tumor at low doses, indicative of Aurora B-kinase inhibition and a reduction in tumor volume. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：1904 / 1909

页数：6

共 19 条

[1] Aurora kinases: shining lights on the therapeutic horizon? [J].

Andrews, PD .

ONCOGENE, 2005, 24 (32) :5005-5015

[2] PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer [J].

Carpinelli, Patrizia ;

Ceruti, Roberta ;

Giorgini, Maria Laura ;

Cappella, Paolo ;

Gianellini, Laura ;

Croci, Valter ;

Degrassi, Anna ;

Texido, Gernma ;

Rocchetti, Maurizio ;

Vianello, Paola ;

Rusconi, Luisa ;

Storici, Paola ;

Zugnoni, Paola ;

Arrigoni, Claudio ;

Soncini, Chiara ;

Alli, Cristina ;

Patton, Veronica ;

Marsiglio, Aurelio ;

Ballinari, Dario ;

Pesenti, Enrico ;

Fancelli, Daniele ;

Moll, Jurgen .

MOLECULAR CANCER THERAPEUTICS, 2007, 6 (12) :3158-3168

[3] Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores [J].

Ditchfield, C ;

Johnson, VL ;

Tighe, A ;

Ellston, R ;

Haworth, C ;

Johnson, T ;

Mortlock, A ;

Keen, N ;

Taylor, SS .

JOURNAL OF CELL BIOLOGY, 2003, 161 (02) :267-280

[4] 1,4,5,6-tetrahydropyrrolo[3,4-c] pyrazoles:: Identification of a potent aurora kinase inhibitor with a favorable antitumor kinase inhibition profile [J].

Fancelli, Daniele ;

Moll, Jurgen ;

Varasi, Mario ;

Bravo, Rodrigo ;

Artico, Roberta ;

Berta, Daniela ;

Bindi, Simona ;

Cameron, Alexander ;

Candiani, Ilaria ;

Cappella, Paolo ;

Carpinelli, Patrizia ;

Croci, Walter ;

Forte, Barbara ;

Giorgini, Maria Laura ;

Klapwijk, Jan ;

Marsiglio, Aurelio ;

Pesenti, Enrico ;

Rocchetti, Maurizio ;

Roletto, Fulvia ;

Severino, Dino ;

Soncini, Chiara ;

Storici, Paola ;

Tonani, Roberto ;

Zugnoni, Paola ;

Vianello, Paola .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (24) :7247-7251

[5] Validating Aurora B as an anti-cancer drug target [J].

Girdler, Fiona ;

Gascoigne, Karen E. ;

Eyers, Patrick A. ;

Hartmuth, Sonya ;

Crafter, Claire ;

Foote, Kevin M. ;

Keen, Nicholas J. ;

Taylor, Stephen S. .

JOURNAL OF CELL SCIENCE, 2006, 119 (17) :3664-3675

[6] VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo [J].

Harrington, EA ;

Bebbington, D ;

Moore, J ;

Rasmussen, RK ;

Ajose-Adeogun, AO ;

Nakayama, T ;

Graham, JA ;

Demur, C ;

Hercend, T ;

Diu-Hercend, A ;

Su, M ;

Golec, JMC ;

Miller, KM .

NATURE MEDICINE, 2004, 10 (03) :262-267

[7] SAR and inhibitor complex structure determination of a novel class of potent and specific Aurora kinase inhibitors [J].

Heron, NM ;

Anderson, M ;

Blowers, DP ;

Breed, J ;

Eden, JM ;

Green, S ;

Hill, GB ;

Johnson, T ;

Jung, FH ;

McMiken, HHJ ;

Mortlock, AA ;

Pannifer, AD ;

Pauptit, RA ;

Pink, J ;

Roberts, NJ ;

Rowsell, S .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (05) :1320-1323

[8]

HERON NM, 2004, Patent No. 2004094410

[9] Two new syntheses of a 4-aminopyrazole: Condensation of an N-substituted vinamidinium salt with a functionalized hydrazine [J].

Hill, George B. ;

Mortlock, Andrew A. .

SYNTHESIS-STUTTGART, 2007, 11 (11) :1697-1701

[10] MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy [J].

Hoar, Kara ;

Chakravarty, Arijit ;

Rabino, Claudia ;

Wysong, Deborah ;

Bowman, Douglas ;

Roy, Natalie ;

Ecsedy, Jeffrey A. .

MOLECULAR AND CELLULAR BIOLOGY, 2007, 27 (12) :4513-4525

← 1 2 →