Yano Shingo, Kazuno Hideki, Sato Tsutomu, Suzuki Norihiko, Emura Tomohiro, Wierzba Konstanty, Yamashita Jun-ichi, Tada Yukio, Yamada Yuji, Fukushima Masakazu, Asao Tetsuji
Hanno Research Center, Taiho Pharmaceutical Co., Ltd, 1-27 Misugidai, Hanno-shi, Saitama 357-8527, Japan.
Bioorg Med Chem. 2004 Jul 1;12(13):3443-50. doi: 10.1016/j.bmc.2004.04.046.
A series of novel 6-methylene-bridged uracil derivatives have been optimized for clinical use as the inhibitors of human thymidine phosphorylase (TP). We describe their synthesis and evaluation. Introduction of a guanidino or an amidino group enhanced the in vitro inhibitory activity of TP comparing with formerly reported inhibitor 1. Their selectivity for TP based on uridine phosphorylase inhibitory activity was also evaluated. Compound 2 (TPI) has been selected for clinical evaluation based on its strong TP inhibition and excellent modulation of 2'-deoxy-5-(trifluoromethyl)uridine (F(3)dThd) pharmacokinetics. As a result, TAS-102 (a combination of F(3)dThd and TPI) is currently in phase 1 clinical studies.
一系列新型的6-亚甲基桥连尿嘧啶衍生物已被优化用于临床，作为人胸苷磷酸化酶（TP）的抑制剂。我们描述了它们的合成与评估。与先前报道的抑制剂1相比，引入胍基或脒基增强了TP的体外抑制活性。还评估了它们基于尿苷磷酸化酶抑制活性对TP的选择性。化合物2（TPI）因其对TP的强抑制作用以及对2'-脱氧-5-（三氟甲基）尿苷（F(3)dThd）药代动力学的出色调节作用而被选用于临床评估。结果，TAS-102（F(3)dThd与TPI的组合）目前正处于1期临床研究阶段。
