Kinesin spindle protein (KSP) inhibitors. Part 2: The design, synthesis, and characterization of 2,4-diaryl-2,5-dihydropyrrole inhibitors of the mitotic kinesin KSP

被引：68

作者：

Fraley, ME ^{[1
]}

Garbaccio, RM

Arrington, KL

Hoffman, WF

Tasber, ES

Coleman, PJ

Buser, CA

Walsh, ES

Hamilton, K

Fernandes, C

Schaber, MD

Lobell, RB

Tao, WK

South, VJ

Yan, YW

Kuo, LC

Prueksaritanont, T

Shu, C

Torrent, M

Heimbrook, DC

Kohl, NE

Huber, HE

Hartman, GD

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Canc Res, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Biol Struct, West Point, PA 19486 USA

[4] Merck Res Labs, Dept Drug Metab, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 07期

关键词：

KSP; hERG; dihydropyrroles; kinesin spindle protein; antimitotics; antiproliferative; anticancer;

D O I：

10.1016/j.bmcl.2006.01.030

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The evolution of 2,4-diaryl-2,5-dihydropyrroles as inhibitors of KSP is described. Introduction of basic amide and urea moieties to the dihydropyrrole nucleus enhanced potency and aqueous solubility, simultaneously, and provided compounds that caused mitotic arrest of A2780 human ovarian carcinoma cells with EC(50)s < 10 nM. Ancillary hERG activity was evaluated for this series of inhibitors. (C) 2006 Elsevier Ltd. All rights reserved.

引用

页码：1775 / 1779

页数：5

共 16 条

[1] Potent N-(1,3-thiazol-2-yl)pyridin-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low affinity for the hERG ion channel
Bilodeau, MT
Balitza, AE
Koester, TJ
Manley, PJ
Rodman, LD
Buser-Doepner, C
Coll, KE
Fernandes, C
Gibbs, JB
Heimbrook, DC
Huckel, WR
Kohl, N
Lynch, JJ
Mao, XZ
McFall, RC
McLoughlin, D
Miller-Stein, CM
Rickert, KW
Sepp-Lorenzino, L
Shipman, JM
Subramanian, R
Thomas, KA
Wong, BK
Yu, S
Hartman, GD
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (25) : 6363 - 6372
[2] Phosphorylation by p34(cdc2) regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo
Blangy, A
Lane, HA
dHerin, P
Harper, M
Kress, M
Nigg, EA
[J]. CELL, 1995, 83 (07) : 1159 - 1169
[3] Carpes MJS, 2000, SYNLETT, P1037
[4] A robotics-based automated assay for inorganic and organic phosphates
Cogan, EB
Birrell, GB
Griffith, OH
[J]. ANALYTICAL BIOCHEMISTRY, 1999, 271 (01) : 29 - 35
[5] Inhibitors of the mitotic kinesin spindle protein
Coleman, PJ
Fraley, ME
[J]. EXPERT OPINION ON THERAPEUTIC PATENTS, 2004, 14 (12) : 1659 - 1667
[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
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
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (08) : 2041 - 2045
[7] Duhl DM, 2005, CURR OPIN DRUG DISC, V8, P431
[8] Microtubule motors in spindle and chromosome motility
Endow, SA
[J]. EUROPEAN JOURNAL OF BIOCHEMISTRY, 1999, 262 (01): : 12 - 18
[9] Motor function in the mitotic spindle
Heald, R
[J]. CELL, 2000, 102 (04) : 399 - 402
[10] Maeda K, 2001, SYNLETT, P1808

← 1 2 →