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Novel tricyclic azepine derivatives: Biological evaluation of pyrimido[4,5-b]-1,4-benzoxazepines, thiazepines, and diazepines as inhibitors of the epidermal growth factor receptor tyrosine kinase

2006; Elsevier BV; Volume: 16; Issue: 19 Linguagem: Inglês

10.1016/j.bmcl.2006.07.031

1464-3405

Leon M. Smith, Wai C. Wong, Alexander S. Kiselyov, Sabina Burdzovic-Wizemann, Yunyu Mao, Yong‐Jiang Xu, Matthew A. J. Duncton, Ki Hyun Kim, Evgueni L. Piatnitski, Jacqueline Doody, Ying Wang, Robin L. Rosler, Daniel L. Milligan, John Columbus, Chris Balagtas, Sui Ping Lee, Andrey Konovalov, Yaron R. Hadari,

Chemical Synthesis and Analysis

Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure-activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC(50) values in the single-digit micromolar to submicromolar range).