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
2012
Hirose, Masaaki | Okaniwa, Masanori | Miyazaki, Tohru | Imada, Takashi | Ohashi, Tomohiro | Tanaka, Yuta | Arita, Takeo | Yabuki, Masato | Kawamoto, Tomohiro | Tsutsumi, Shunichirou | Sumita, Akihiko | Takagi, Terufumi | Sang, Bi-Ching | Yano, Jason | Aertgeerts, Kathleen | Yoshida, Sei | Ishikawa, Tomoyasu
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.
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