Design and Synthesis of Pyrrolo[3,2-d]pyrimidine Human Epidermal Growth Factor Receptor 2 (HER2)/Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors: Exploration of Novel Back-Pocket Binder

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• 作者：Youichi Kawakita ; Hiroshi Banno ; Tomohiro Ohashi ; Toshiya Tamura ; Tadashi Yusa ; Akiko Nakayama ; Hiroshi Miki ; Hidehisa Iwata ; Hidenori Kamiguchi ; Toshimasa Tanaka ; Noriyuki Habuka ; Satoshi Sogabe ; Yoshikazu Ohta ; Tomoyasu Ishikawa
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 26, 2012
• 年：2012
• 卷：55
• 期：8
• 页码：3975-3991
• 全文大小：810K
• 年卷期：v.55,no.8(April 26, 2012)
• ISSN：1520-4804

文摘

To develop novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) kinase inhibitors, we explored pyrrolo[3,2-d]pyrimidine derivatives bearing bicyclic fused rings designed to fit the back pocket of the HER2/EGFR proteins. Among them, the 1,2-benzisothiazole (42m) ring was selected as a suitable back pocket binder because of its potent HER2/EGFR binding and cell growth inhibitory (GI) activities and pseudoirreversibility (PI) profile as well as good bioavailability (BA). Ultimately, we arrived at our preclinical candidate 51m by optimization of the N-5 side chain to improve CYP inhibition and metabolic stability profiles without a loss of potency (HER2/EGFR inhibitory activity, IC₅₀, 0.98/2.5 nM; and GI activity BT-474 cells, GI₅₀, 2.0 nM). Reflecting the strong in vitro activities, 51m exhibited potent tumor regressive efficacy against both HER2- and EGFR-overexpressing tumor (4鈥?ST and CAL27) xenograft models in mice at oral doses of 50 mg/kg and 100 mg/kg.