Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds

  • J Med Chem. 2012 Apr 12;55(7):3452-78. doi: 10.1021/jm300126x.
Masanori Okaniwa  1 ,  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
Affiliations
  • 1. Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. [email protected]
PMID: 22376051 DOI: 10.1021/jm300126x
Abstract

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.

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