Synthesis and SAR of pyrrolotriazine-4-one based Eg5 inhibitors

被引：45

作者：

Kim, Kyoung Soon ^{[1
]}

Lu, Songfeng ^{[1
]}

Cornelius, Lyndon A. ^{[1
]}

Lombardo, Louis J. ^{[1
]}

Borzilleri, Robert M. ^{[1
]}

Schroeder, Gretchen M. ^{[1
]}

Sheng, Christopher ^{[1
]}

Rovnyak, George ^{[1
]}

Crews, Donald ^{[1
]}

Schmidt, Robert J. ^{[1
]}

Williams, David K. ^{[1
]}

Bhide, Rajeev S. ^{[1
]}

Traeger, Sarah C. ^{[1
]}

McDonnell, Patricia A. ^{[1
]}

Mueller, Luciano ^{[1
]}

Sheriff, Steven ^{[1
]}

Newitt, John A. ^{[1
]}

Pudzianowski, Andrew T. ^{[1
]}

Yang, Zheng ^{[1
]}

Wild, Robert ^{[1
]}

Lee, Frances Y. ^{[1
]}

Batorsky, Roberta ^{[1
]}

Ryder, James S. ^{[1
]}

Ortega-Nanos, Marie ^{[1
]}

Shen, Henry ^{[1
]}

Gottardis, Marco ^{[1
]}

Roussell, Deborah L. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Pharmaceut Res Inst, Dept Drug Discovery, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 15期

关键词：

Eg5; pyrrolotraizine; microtubule; kinesin; anti-tumor; cytotoxic;

D O I：

10.1016/j.bmcl.2006.05.037

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Synthesis and SAR of substituted pyrrolotriazine-4-one analogues as Eg5 inhibitors are described. Many of these analogues displayed potent inhibitory activities in the Eg5 ATPase and A2780 cell proliferation assays. In addition, pyrrolotriazine-4-one analogue 26 demonstrated in vivo efficacy in an iv P388 murine leukemia model. Both NMR and X-ray crystallographic studies revealed that these analogues bind to an allosteric site on the Eg5 protein. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：3937 / 3942

页数：6

共 26 条

[1]

BELANGER P, 1979, TETRAHEDRON LETT, P2505

[2] Mitotic kinesins: Prospects for antimitotic drug discovery [J].

Bergnes, G ;

Brejc, K ;

Belmont, L .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2005, 5 (02) :127-145

[3]

Blagosklonny MV, 1999, INT J CANCER, V83, P151, DOI 10.1002/(SICI)1097-0215(19991008)83:2<151::AID-IJC1>3.0.CO

[4]

2-5

[5] Phosphorylation by p34(cdc2) regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo [J].

Blangy, A ;

Lane, HA ;

dHerin, P ;

Harper, M ;

Kress, M ;

Nigg, EA .

CELL, 1995, 83 (07) :1159-1169

[6] Kinesin spindle protein (KSP) inhibitors. Part 1: The discovery of 3,5-diaryl-4,5-dihydropyrazoles as potent and selective inhibitors of the mitotic kinesin KSP [J].

Cox, CD ;

Breslin, MJ ;

Brenda, JM ;

Coleman, PJ ;

Buser, CA ;

Walsh, ES ;

Hamilton, K ;

Huber, HE ;

Kohl, NE ;

Torrent, M ;

Yan, YW ;

Kuo, LC ;

Hartman, GD .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (08) :2041-2045

[7]

Dutcher JP, 2000, J CLIN PHARMACOL, V40, P1079

[8]

FINNER JT, Patent No. 0130768

[9] Opposing motor activities are required for the organization of the mammalian mitotic spindle pole [J].

Gaglio, T ;

Saredi, A ;

Bingham, JB ;

Hasbani, MJ ;

Gill, SR ;

Schroer, TA ;

Compton, DA .

JOURNAL OF CELL BIOLOGY, 1996, 135 (02) :399-414

[10] HALOGENATION OF METHYL PYRROLE-2-CARBOXYLATE AND OF SOME RELATED PYRROLES [J].

HODGE, P ;

RICKARDS, RW .

JOURNAL OF THE CHEMICAL SOCIETY, 1965, (JAN) :459-&

← 1 2 3 →