1125632-63-4Relevant academic research and scientific papers
Design and synthesis of novel DFG-Out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds
Okaniwa, Masanori,Hirose, Masaaki,Imada, Takashi,Ohashi, Tomohiro,Hayashi, Youko,Miyazaki, Tohru,Arita, Takeo,Yabuki, Masato,Kakoi, Kazuyo,Kato, Juran,Takagi, Terufumi,Kawamoto, Tomohiro,Yao, Shuhei,Sumita, Akihiko,Tsutsumi, Shunichirou,Tottori, Tsuneaki,Oki, Hideyuki,Sang, Bi-Ching,Yano, Jason,Aertgeerts, Kathleen,Yoshida, Sei,Ishikawa, Tomoyasu
experimental part, p. 3452 - 3478 (2012/06/17)
To develop RAF/VEGFR2 inhibitors that bind to the inactive DFG-out conformation, we conducted structure-based drug design using the X-ray cocrystal structures of BRAF, starting from an imidazo[1,2-b]pyridazine derivative. We designed various [5,6]-fused bicyclic scaffolds (ring A, 1-6) possessing an anilide group that forms two hydrogen bond interactions with Cys532. Stabilizing the planarity of this anilide and the nitrogen atom on the six-membered ring of the scaffold was critical for enhancing BRAF inhibition. The selected [1,3]thiazolo[5,4-b]pyridine derivative 6d showed potent inhibitory activity in both BRAF and VEGFR2. Solid dispersion formulation of 6d (6d-SD) maximized its oral absorption in rats and showed significant suppression of ERK1/2 phosphorylation in an A375 melanoma xenograft model in rats by single administration. Tumor regression (T/C = -7.0%) in twice-daily repetitive studies at a dose of 50 mg/kg in rats confirmed that 6d is a promising RAF/VEGFR2 inhibitor showing potent anticancer activity.
HETEROCYCLIC COMPOUND AND USE THEREOF
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Page/Page column 39, (2011/10/12)
A compound represented by formula (I) or a salt thereof, which has a potent Raf inhibitory activity. In formula (I), R1 represents an optionally substituted C1-6 alkyl, etc.; X represents —O— or —NR2— (wherein R2 represents a hydrogen atom or a C1-6 alkyl); Y represents a group represented by formula 2 (2ii or 2ii) (wherein ring A represents an optionally substituted benzene ring; Z represents a group represented by (1) —NR3CO—W1—, (2) —NR3CO—W1—O—, (3) —NR3CO—W1—O—W2—, (4) —NR3CO—W1—S—, (5) —NR3CO—W1—NR4—, (6) —NR3COO—, (7) —NR3COO—W1—, (8) —NR3CO—CO—, or (9) —NR3CONR4— (wherein R3 and R4 each represents a hydrogen atom, etc., and W1 and W2 each represents an optionally substituted C1-6 alkylene, etc.); and R5 represents an optionally substituted five- or six-membered ring group.
