Design and synthesis of pyrrolo[3,2-d]pyrimidine HER2/EGFR dual inhibitors: Improvement of the physicochemical and pharmacokinetic profiles for potent in vivo anti-tumor efficacy

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• 作者：Youichi Kawakita ; Kazuhiro Miwa ; Masaki Seto ; Hiroshi Banno ; Yoshikazu Ohta ; Toshiya Tamura ; Tadashi Yusa ; Hiroshi Miki ; Hidenori Kamiguchi ; Yukihiro Ikeda ; Toshimasa Tanaka ; Keiji Kamiyama ; Tomoyasu Ishikawa
• 关键词：HER2 (erbB2)/EGFR (erbB1) ; human epidermal growth factor receptor 2/epidermal growth factor receptor ; PK profile ; pharmacokinetic profile ; IC ; inhibitory concentration ; GI ; growth inhibitiory ; DMPK ; drug metabolism and pharmacokinetic profile ; MOA ; mechan
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：15 October, 2012
• 年：2012
• 卷：20
• 期：20
• 页码：6171-6180
• 全文大小：681 K

文摘

During the course of our studies on a novel HER2/EGFR dual inhibitor (TAK-285), we found an alternative potent pyrrolo[3,2-d]pyrimidine compound (1a). To enhance the pharmacokinetic (PK) profile of this compound, we conducted chemical modifications into its N-5 side chain and conversion of the chemically modified compounds into their salts. Among them, 2cb, the tosylate salt of compound 2c, showed potent HER2/EGFR kinase inhibitory activity (IC₅₀: 11/11 nM) and cellular growth inhibitory activity (BT-474 cell GI₅₀: 56 nM) with a good drug metabolism and PK (DMPK) profile. Furthermore, 2cb exhibited significant in vivo antitumor efficacy in both mouse and rat xenograft models with transplanted 4-1ST gastric cancer cell lines (mouse, T/C = 0 % , 2cb po bid at 100 mg/kg; rat, T/C: -1 % , 2cb po bid at 25 mg/kg).