Takeo Arita

Publications (3)10.44 Total impact

• Article: Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors: 3. Evaluation of 5-amino-linked thiazolo[5,4-d]pyrimidine and thiazolo[5,4-b]pyridine derivatives.

  Masaaki Hirose, Masanori Okaniwa, Tohru Miyazaki, Takashi Imada, Tomohiro Ohashi, Yuta Tanaka, Takeo Arita, Masato Yabuki, Tomohiro Kawamoto, Shunichirou Tsutsumi, Akihiko Sumita, Terufumi Takagi, Bi-Ching Sang, Jason Yano, Kathleen Aertgeerts, Sei Yoshida, Tomoyasu Ishikawa
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  ABSTRACT: Our aim was to discover RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors that possess strong activity and sufficient oral absorption, and thus, we selected a 5-amino-linked thiazolo[5,4-d]pyrimidine derivative as the lead compound because of its potential kinase inhibitory activities and its desired solubility. The novel tertiary 1-cyano-1-methylethoxy substituent was designed to occupy the hydrophobic region of 'back pocket' of BRAF on the basis of the X-ray co-crystal structure data of BRAF. In addition, we found that N-methylation of the amine linker could control the twisted molecular conformation leading to improved solubility. These approaches produced N-methyl thiazolo[5,4-b]pyridine-5-amine derivative 5. To maximize the in vivo efficacy, we attempted salt formation of 5. Our result indicated that the besylate monohydrate salt form (5c) showed significant improvement of both solubility and oral absorption. Owing to the improved physicochemical properties, compound 5c demonstrated regressive antitumor efficacy in a HT-29 xenograft model.
  Bioorganic & medicinal chemistry 07/2012; 20(18):5600-15. · 2.82 Impact Factor
• Article: Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors: 2. Synthesis and characterization of a novel imide-type prodrug for improving oral absorption.

  Masanori Okaniwa, Takashi Imada, Tomohiro Ohashi, Tohru Miyazaki, Takeo Arita, Masato Yabuki, Akihiko Sumita, Shunichirou Tsutsumi, Keiko Higashikawa, Terufumi Takagi, Tomohiro Kawamoto, Yoshitaka Inui, Sei Yoshida, Tomoyasu Ishikawa
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  ABSTRACT: As an alternative to the previously reported solid dispersion formulation for enhancing the oral absorption of thiazolo[5,4-b]pyridine 1, we investigated novel N-acyl imide prodrugs of 1 as RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. Introducing N-acyl promoieties at the benzanilide position gave chemically stable imides. N-tert-Butoxycarbonyl (Boc) introduced imide 6 was a promising prodrug, which was converted to the active compound 1 after its oral administration in mice. Cocrystals of 6 with AcOH (6b) possessed good physicochemical properties with moderate thermodynamic solubility (19μg/mL). This crystalline prodrug 6b was rapidly and enzymatically converted into 1 after its oral absorption in mice, rats, dogs, and monkeys. Prodrug 6b showed in vivo antitumor regressive efficacy (T/C=-6.4%) in an A375 melanoma xenograft model in rats. Hence, we selected 6b as a promising candidate and are performing further studies. Herein, we report the design, synthesis, and characterization of novel imide-type prodrugs.
  Bioorganic & medicinal chemistry 06/2012; 20(15):4680-92. · 2.82 Impact Factor
• Article: Design and synthesis of novel DFG-out RAF/vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclic scaffolds.

  Masanori Okaniwa, Masaaki Hirose, Takashi Imada, Tomohiro Ohashi, Youko Hayashi, Tohru Miyazaki, Takeo Arita, Masato Yabuki, Kazuyo Kakoi, Juran Kato, [......], Shuhei Yao, Akihiko Sumita, Shunichirou Tsutsumi, Tsuneaki Tottori, Hideyuki Oki, Bi-Ching Sang, Jason Yano, Kathleen Aertgeerts, Sei Yoshida, Tomoyasu Ishikawa
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  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.
  Journal of Medicinal Chemistry 02/2012; 55(7):3452-78. · 4.80 Impact Factor