论文信息 - 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.

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.

We describe the identification of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-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.

[1] M. Meyerson,et al. Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[2] D. Boschelli,et al. Inhibition of Src kinase activity by 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-heteroaryl-thieno[3,2-b]pyridine-6-carbonitriles. , 2005, Bioorganic & medicinal chemistry letters.

[3] S. Curley,et al. Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer. , 1993, The Journal of clinical investigation.

[4] G. Gallick,et al. Src family kinases in tumor progression and metastasis , 2003, Cancer and Metastasis Reviews.

[5] T. Ay,et al. SRC: Regulation, Role in Human Carcinogenesis and Pharmacological Inhibitors , 2004 .

[6] Fabrizio Manetti,et al. A combination of docking/dynamics simulations and pharmacophoric modeling to discover new dual c-Src/Abl kinase inhibitors. , 2006, Journal of medicinal chemistry.

[7] P. Schwartzberg,et al. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. , 1999, Molecular cell.

[8] S. Ashley,et al. Inhibition of tyrosine kinase Src suppresses pancreatic cancer invasiveness. , 2003, Surgery.

[9] Michael Chopp,et al. Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke , 2001, Nature Medicine.

[10] J. Trevino,et al. SRC inhibitors as potential therapeutic agents for human cancers. , 2006, Mini reviews in medicinal chemistry.

[11] N. Himes,et al. Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction. , 2004, The Journal of clinical investigation.

[12] M. Eriksson,et al. Studies of drug binding to plasma proteins using a variant of equilibrium dialysis. , 2005, Journal of Pharmaceutical and Biomedical Analysis.

[13] M. Missbach,et al. Src inhibitors: drugs for the treatment of osteoporosis, cancer or both? , 2000, Trends in pharmacological sciences.

[14] Y. Lim,et al. Phosphorylation of Focal Adhesion Kinase at Tyrosine 861 Is Crucial for Ras Transformation of Fibroblasts* , 2004, Journal of Biological Chemistry.

[15] M. Modugno,et al. 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. , 2006, Journal of medicinal chemistry.

[16] S. Hanks,et al. Focal adhesion kinase tyrosine-861 is a major site of phosphorylation by Src. , 1996, Biochemical and biophysical research communications.

[17] Joel Renick,et al. Discovery and preliminary structure-activity relationship studies of novel benzotriazine based compounds as Src inhibitors. , 2006, Bioorganic & medicinal chemistry letters.

[18] R. Bohacek,et al. Bone-targeted 2,6,9-trisubstituted purines: novel inhibitors of Src tyrosine kinase for the treatment of bone diseases. , 2003, Bioorganic & medicinal chemistry letters.

[19] Philippe Soriano,et al. Knockouts of Src-family kinases: stiff bones, wimpy T cells, and bad memories. , 1996, Genes & development.

[20] G. C. Fu,et al. A versatile method for Suzuki cross-coupling reactions of nitrogen heterocycles. , 2006, Angewandte Chemie.

[21] T. Yeatman,et al. Role of Src expression and activation in human cancer , 2000, Oncogene.

[22] D. Boschelli,et al. Synthesis and Src kinase inhibitory activity of 2-phenyl- and 2-thienyl-7-phenylaminothieno[3,2-b]pyridine-6-carbonitriles. , 2005, Journal of medicinal chemistry.

[23] E. G. Mata,et al. The polymer-supported and combinatorial synthesis of beta-lactam compounds: an update. , 2006, Mini reviews in medicinal chemistry.

[24] D. Boschelli,et al. Identification of 7-phenylaminothieno- [3,2-b]pyridine-6-carbonitriles as a new class of Src kinase inhibitors. , 2004, Journal of medicinal chemistry.

[25] Susan Adams,et al. Structural Basis of Src Tyrosine Kinase Inhibition with a New Class of Potent and Selective Trisubstituted Purine‐based Compounds , 2006, Chemical biology & drug design.

[26] F. Arndt. Ringschluß zwischen Nitro- und Aminogruppe unter Bildung von Triazinen , 1913 .

[27] Timothy J. Yeatman,et al. A renaissance for SRC , 2004, Nature Reviews Cancer.

[28] S. Buchwald,et al. Expedited palladium-catalyzed amination of aryl nonaflates through the use of microwave-irradiation and soluble organic amine bases. , 2006, The Journal of organic chemistry.

[29] Peter F Thall,et al. Activated SRC protein tyrosine kinase is overexpressed in late-stage human ovarian cancers. , 2003, Gynecologic oncology.

[30] M. Bednarski,et al. Tumor Regression by Targeted Gene Delivery to the Neovasculature , 2002, Science.