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
2012
Kawakita, Youichi | Miwa, Kazuhiro | Seto, Masaki | Banno, Hiroshi | Ohta, Yoshikazu | Tamura, Toshiya | Yusa, Tadashi | Miki, Hiroshi | Kamiguchi, Hidenori | Ikeda, Yukihiro | Tanaka, Toshimasa | Kamiyama, Keiji | Ishikawa, Tomoyasu
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: 11/11nM) and cellular growth inhibitory activity (BT-474 cell GI₅₀: 56nM) 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 100mg/kg; rat, T/C: -1%, 2cb po bid at 25mg/kg).
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