Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide (pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor

被引:308
作者
Harris, Philip A.
Boloor, Amogh
Cheung, Mui
Kumar, Rakesh
Crosby, Renae M. [1 ]
Davis-Ward, Ronda G. [1 ]
Epperly, Andrea H. [1 ]
Hinkle, Kevin W. [1 ]
Hunter, Robert N., III [1 ]
Johnson, Jennifer H. [1 ]
Knick, Victoria B. [1 ]
Laudeman, Christopher P. [1 ]
Luttrell, Deirdre K.
Mook, Robert A. [1 ]
Nolte, Robert T. [1 ]
Rudolph, Sharon K. [1 ]
Szewczyk, Jerzy R. [1 ]
Truesdale, Anne T.
Veal, James M.
Wang, Liping [1 ]
Stafford, Jeffrey A.
机构
[1] GlaxoSmithKline, Res Triangle Pk, NC 27709 USA
关键词
D O I
10.1021/jm800566m
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N-4-(2,3-dimethyl-2H-indazol-6-yl)-N-4-methyl-N-2-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors.
引用
收藏
页码:4632 / 4640
页数:9
相关论文
共 21 条
[1]   A review of the latest clinical compounds to inhibit VEGF in pathological angiogenesis [J].
Baka, Sofia ;
Clamp, Andrew R. ;
Jayson, Gordon C. .
EXPERT OPINION ON THERAPEUTIC TARGETS, 2006, 10 (06) :867-876
[2]   SYNTHESIS OF INDOLES VIA RING-CLOSURE OF 2-ALKYLNITROANILINE DERIVATIVES [J].
BERGMAN, J ;
SAND, P .
TETRAHEDRON, 1990, 46 (17) :6085-6112
[3]   Comparison of the biochemical and kinetic properties of the type 1 receptor tyrosine kinase intracellular domains - Demonstration of differential sensitivity to kinase inhibitors [J].
Brignola, PS ;
Lackey, K ;
Kadwell, SH ;
Hoffman, C ;
Horne, E ;
Carter, HL ;
Stuart, JD ;
Blackburn, K ;
Moyer, MB ;
Alligood, KJ ;
Knight, WB ;
Wood, ER .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (02) :1576-1585
[4]  
Caprioni Francesco, 2007, Future Oncol, V3, P141, DOI 10.2217/14796694.3.2.141
[5]   Sunitinib: From rational design to clinical efficacy [J].
Chow, Laura Q. M. ;
Eckhardt, S. Gail .
JOURNAL OF CLINICAL ONCOLOGY, 2007, 25 (07) :884-896
[6]  
DeLano W. L., 2002, PYMOL
[7]   Antitumour efficacy of VEGFR2 tyrosine kinase inhibitor correlates with expression of VEGF and its receptor VEGFR2 in tumour models [J].
Dev, IK ;
Dornsife, RE ;
Hopper, TM ;
Onori, JA ;
Miller, CG ;
Harrington, LE ;
Dold, KM ;
Mullin, RJ ;
Johnson, JH ;
Crosby, RM ;
Truesdale, AT ;
Epperly, AH ;
Hinkle, KW ;
Cheung, M ;
Stafford, JA ;
Luttrell, DK ;
Kumar, R .
BRITISH JOURNAL OF CANCER, 2004, 91 (07) :1391-1398
[8]   Opinion - Angiogenesis: an organizing principle for drug discovery? [J].
Folkman, Judah .
NATURE REVIEWS DRUG DISCOVERY, 2007, 6 (04) :273-286
[9]   Discovery and evaluation of 2-anilino-5-aryloxazoles as a novel class of VEGFR2 kinase inhibitors [J].
Harris, PA ;
Cheung, M ;
Hunter, RN ;
Brown, ML ;
Veal, JM ;
Nolte, RT ;
Wang, LP ;
Liu, W ;
Crosby, RM ;
Johnson, JH ;
Epperly, AH ;
Kumar, R ;
Luttrell, DK ;
Stafford, JA .
JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (05) :1610-1619
[10]   Sorafenib for the treatment of advanced renal cell carcinoma [J].
Kane, Robert C. ;
Farrell, Ann T. ;
Saber, Haleh ;
Tang, Shenghui ;
Williams, Gene ;
Jee, Josephine M. ;
Liang, Chengyi ;
Booth, Brian ;
Chidambaram, Nallaperumal ;
Morse, David ;
Sridhara, Rajeshwari ;
Garvey, Patricia ;
Justice, Robert ;
Pazdur, Richard .
CLINICAL CANCER RESEARCH, 2006, 12 (24) :7271-7278