Discovery of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine - a potent, orally active Src kinase inhibitor with anti-tumor activity in preclinical assays

被引：51

作者：

Noronha, Glenn

Barrett, Kathy

Boccia, Antonio

Brodhag, Tessa

Cao, Jianguo

Chow, Chun P.

Dneprovskaia, Elena

Doukas, John

Fine, Richard

Gong, Xianchang

Gritzen, Colleen

Gu, Hong

Hanna, Ehab

Hood, John D.

Hu, Steven

Kang, Xinshan

Key, Jann

Klebansky, Boris

Kousba, Ahmed

Li, Ge

Lohse, Dan

Mak, Chi Ching

McPherson, Andrew

Palanki, Moorthy S. S.

Pathak, Ved P.

Renick, Joel

Shi, Feng

Soll, Richard

Splittgerber, Ute

Stoughton, Silva

Tang, Suhan

Yee, Shiyin

Zeng, Binqi

Zhao, Ningning

Zhu, Hong

机构：

[1] TargeGen Inc, San Diego, CA 92121 USA

[2] BioPredict Inc, Oradell, NJ 07649 USA

[3] Wuxi PharmaTech Ltd, Shanghai, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 03期

关键词：

Src inhibitor; cancer; kinase inhibitor; benzotriazines;

D O I：

10.1016/j.bmcl.2006.11.006

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We describe the identification of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-l-ylethoxy)phenyl]amine (3), a potent, orally active Src inhibitor with desirable PK properties, demonstrated activity in human tumor cell lines and in animal models of tumor growth. (c) 2006 Elsevier Ltd. All rights reserved.

引用

收藏

页码：602 / 608

页数：7

相关论文

共 34 条

[1] Closure between nitro- and amino groups under the formation of triazine [J].

Arndt, F .

BERICHTE DER DEUTSCHEN CHEMISCHEN GESELLSCHAFT, 1913, 46 :3522-3530

[2] Inhibition of Src kinase activity by 7-[(2,4-dichloro-5-methoxyphenyl)-amino]-2-heteroaryl-thieno[3,2-b]pyridine-6-carbonitriles [J].

Boschelli, DH ;

Wu, BQ ;

Sosa, ACB ;

Chen, JJ ;

Golas, JM ;

Boschelli, F .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (21) :4681-4684

[3] Synthesis and Src kinase inhibitory activity of 2-phenyl- and 2-thienyl-7-phenylaminothieno[3,2-b]pyridine-6-carbonitriles [J].

Boschelli, DH ;

Wu, B ;

Sosa, ACB ;

Durutlic, H ;

Chen, JJ ;

Wang, Y ;

Golas, JM ;

Lucas, J ;

Boschelli, F .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (11) :3891-3902

[4] Identification of 7-phenylaxaminothieno[3,2-b]pyridine-6-carbonitriles as a new class of Src kinase inhibitors [J].

Boschelli, DH ;

Wu, BQ ;

Sosa, ACB ;

Durutlic, H ;

Ye, F ;

Raifeld, Y ;

Golas, JM ;

Boschelli, F .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (27) :6666-6668

[5] Focal adhesion kinase tyrosine-861 is a major site of phosphorylation by Src [J].

Calalb, MB ;

Zhang, XE ;

Polte, TR ;

Hanks, SK .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1996, 228 (03) :662-668

[6] Pyrazolo[3,4-d]pyrimidines as potent antiproliferative and proapoptotic agents toward A431 and 8701-BC cells in culture via inhibition of c-Src phosphorylation [J].

Carraro, F ;

Naldini, A ;

Pucci, A ;

Locatelli, GA ;

Maga, G ;

Schenone, S ;

Bruno, O ;

Ranise, A ;

Bondavalli, F ;

Brullo, C ;

Fossa, P ;

Menozzi, G ;

Mosti, L ;

Modugno, M ;

Tintori, C ;

Manetti, F ;

Botta, M .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (05) :1549-1561

[7] Structural basis of Src tyrosine kinase inhibition with a new class of potent and selective trisubstituted purine-based compounds [J].

Dalgarno, D ;

Stehle, T ;

Narula, S ;

Schelling, P ;

van Schravendijk, MR ;

Adams, S ;

Andrade, L ;

Keats, J ;

Ram, M ;

Jin, L ;

Grossman, T ;

MacNeil, I ;

Metcalf, C ;

Shakespeare, W ;

Wang, Y ;

Keenan, T ;

Sundaramoorthi, R ;

Bohacek, R ;

Weigele, M ;

Sawyer, T .

CHEMICAL BIOLOGY & DRUG DESIGN, 2006, 67 (01) :46-57

[8] Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability [J].

Eliceiri, BP ;

Paul, R ;

Schwartzberg, PL ;

Hood, JD ;

Leng, J ;

Cheresh, DA .

MOLECULAR CELL, 1999, 4 (06) :915-924

[9] Studies of drug binding to plasma proteins using a variant of equilibrium dialysis [J].

Eriksson, MAL ;

Gabrielsson, J ;

Nilsson, LB .

JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, 2005, 38 (03) :381-389

[10]

HONOLD K, 2006, Patent No. 2006066913

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