N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck:: Indazoles as phenol isosteres with improved pharmacokinetics

被引：42

作者：

Bamborough, Paul ^{[1
]}

Angell, Richard M. ^{[1
]}

Bhamra, Inder ^{[1
]}

Brown, David ^{[1
]}

Bull, James ^{[1
]}

Christopher, John A. ^{[1
]}

Cooper, Anthony W. J. ^{[1
]}

Fazal, Lynsey H. ^{[1
]}

Giordano, Ilaria ^{[1
]}

Hind, Lucy ^{[1
]}

Patel, Vipulkumar K. ^{[1
]}

Ranshaw, Lisa E. ^{[1
]}

Sims, Martin J. ^{[1
]}

Skone, Philip A. ^{[1
]}

Smith, Kathryn J. ^{[1
]}

Vickerstaff, Emma ^{[1
]}

Washington, Melanie ^{[1
]}

机构：

[1] GlaxoSmithKline R&D, Med Res Ctr, Stevenage SG1 2NY, Herts, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 15期

关键词：

2,4-dianilino pyrimidines; Lck inhibitors; p56Lck inhibitors; protein kinase inhibitors;

D O I：

10.1016/j.bmcl.2007.04.029

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

2,4-Dianilino pyrimidines are well-known inhibitors of tyrosine kinases including lymphocyte specific kinase (Lek). Structure-activity relationships at the 4-position are discussed and rationalised. Examples bearing a 2-methyl-5-hydroxyaniline substituent at the 4-position were especially potent but showed poor oral pharmacokinetics. Replacement of this substituent by 4-amino(5methyl-IH-indazole) yielded compounds with comparable enzyme potency and improved pharmacokinetic properties. (c) 2007 Elsevier Ltd. All rights reserved.

引用

页码：4363 / 4368

页数：6

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