The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901

被引：232

作者：

Barrett, Stephen D. ^{[1
]}

Bridges, Alexander J. ^{[1
]}

Dudley, David T. ^{[2
]}

Saltiel, Alan R. ^{[2
]}

Fergus, James H. ^{[2
]}

Flamme, Cathlin M. ^{[1
]}

Delaney, Amy M. ^{[2
]}

Kaufman, Michael ^{[1
]}

LePage, Sophie ^{[2
]}

Leopold, Wilbur R. ^{[2
]}

Przybranowski, Sally A. ^{[2
]}

Sebolt-Leopold, Judith ^{[2
]}

Van Becelaere, Keri ^{[2
]}

Doherty, Annette M. ^{[1
]}

Kennedy, Robert M. ^{[1
]}

Marston, Dan ^{[1
]}

Howard, W. Allen, Jr. ^{[1
]}

Smith, Yvonne ^{[1
]}

Warmus, Joseph S. ^{[1
,3
]}

Tecle, Haile ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Dept Chem, Ann Arbor, MI 48105 USA

[2] Pfizer Global Res & Dev, Oncol Pharmacol, Ann Arbor, MI 48105 USA

[3] Pfizer Global Res & Dev, Groton, CT 06340 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 24期

关键词：

MEK; CI-1040; PD; 0325901; Mitogen-activated protein kinase; MAP/ERK kinase; ERK; Hydroxamate ester; Benzhydroxamate ester; Oncology; Anthranilic acid;

D O I：

10.1016/j.bmcl.2008.10.054

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of benzhydroxamate esters derived from their precursor anthranilic acids have been prepared and have been identified as potent MEK inhibitors. 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide, CI-1040, was the first MEK inhibitor to demonstrate in vivo activity in preclinical animal models and subsequently became the first MEK inhibitor to enter clinical trial. CI-1040 suffered however from poor exposure due to its poor solubility and rapid clearance, and as a result, development of the compound was terminated. Optimization of the diphenylamine core and modi. cation of the hydroxamate side chain for cell potency, solubility, and exposure with oral delivery resulted in the discovery of the clinical candidate N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide PD 0325901. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：6501 / 6504

页数：4

共 18 条

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