Design and synthesis of novel pyrimido[4,5-b]azepine derivatives as HER2/EGFR dual inhibitors

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• 作者：Youichi Kawakita ; ^{youichi.kawakita@takeda.com} ; Masaki Seto ; Tomohiro Ohashi ; Toshiya Tamura ; Tadashi Yusa ; Hiroshi Miki ; Hidehisa Iwata ; Hidenori Kamiguchi ; Toshimasa Tanaka ; Satoshi Sogabe ; Yoshikazu Ohta ; Tomoyasu Ishikawa ; ^{tomoyasu.ishikawa@takeda.com}
• 关键词：1H NMR ; proton nuclear magnetic resonance ; DMF ; N ; N-dimethylformamide ; EGFR ; epidermal growth factor receptor ; EDC ; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ; EtOAc ; ethyl acetate ; EtOH ; ethanol ; GI ; growth inhibitory ; HCl ; hydrochloric
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：15 April, 2013
• 年：2013
• 卷：21
• 期：8
• 页码：2250-2261
• 全文大小：1623 K

文摘

A novel 7,6 fused bicyclic scaffold, pyrimido[4,5-b]azepine was designed to fit into the ATP binding site of the HER2/EGFR proteins. The synthesis of this scaffold was accomplished by an intramolecular Claisen-type condensation. As the results of optimization lead us to 4-anilino and 6-functional groups, we discovered 6-substituted amide derivative 19b, which has a 1-benzothiophen-4-yloxy group attached to the 4-anilino group. An X-ray co-crystal structure of 19b with EGFR demonstrated that the N-1 and N-3 nitrogens of the pyrimido[4,5-b]azepine scaffold make hydrogen-bonding interactions with the main chain NH of Met793 and the side chain of Thr854 via a water-mediated hydrogen bond network, respectively. In addition, the NH proton at the 9-position makes an additional hydrogen bond with the carbonyl group of Met793, as we expected. Compound 19b revealed potent HER2/EGFR kinase (IC₅₀: 24/36 nM) and BT474 cell growth (GI₅₀: 18 nM) inhibitory activities based on its pseudo-irreversible (PI) profile.