Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Bioorg Med Chem. 2012 Oct 15;20(20):6171-80. doi: 10.1016/j.bmc.2012.08.002. Epub 2012 Aug 25.
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 (IC(50): 11/11 nM) and cellular growth inhibitory activity (BT-474 cell GI(50): 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).
在我们对一种新型 HER2/EGFR 双重抑制剂（TAK-285）进行研究的过程中，我们发现了一种具有潜力的新型吡咯并[3,2-d]嘧啶化合物（1a）。为了增强该化合物的药代动力学（PK）特性，我们对其 N-5 侧链进行了化学修饰，并将化学修饰后的化合物转化为其盐。其中，化合物 2c 的 tosylate 盐 2cb 表现出很强的 HER2/EGFR 激酶抑制活性（IC50：11/11 nM）和细胞生长抑制活性（BT-474 细胞 GI50：56 nM），具有良好的药物代谢和 PK（DMPK）特性。此外，2cb 在携带 4-1ST 胃癌细胞系的小鼠和大鼠异种移植模型中表现出显著的体内抗肿瘤疗效（小鼠，T/C=0%，2cb 口服，100 mg/kg，bid；大鼠，T/C：-1%，2cb 口服，25 mg/kg，bid）。
