Design and Synthesis of Novel DFG-Out RAF/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Inhibitors. 1. Exploration of [5,6]-Fused Bicyclic Scaffolds

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• 作者：Masanori Okaniwa ; Masaaki Hirose ; Takashi Imada ; Tomohiro Ohashi ; Youko Hayashi ; Tohru Miyazaki ; Takeo Arita ; Masato Yabuki ; Kazuyo Kakoi ; Juran Kato ; Terufumi Takagi ; Tomohiro Kawamoto ; Shuhei Yao ; Akihiko Sumita ; Shunichirou Tsutsumi ; Tsuneaki Tottori ; Hideyuki Oki ; Bi-Ching Sang ; Jason Yano ; Kathleen Aertgeerts ; Sei Yoshida ; Tomoyasu Ishikawa
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 12, 2012
• 年：2012
• 卷：55
• 期：7
• 页码：3452-3478
• 全文大小：1146K
• 年卷期：v.55,no.7(April 12, 2012)
• ISSN：1520-4804

文摘

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鈥?b>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 = 鈭?.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.