Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 2: optimization of inhibitors of human thymidine phosphorylase and their selectivity with uridine phosphorylase |
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Authors: | Yano Shingo Kazuno Hideki Sato Tsutomu Suzuki Norihiko Emura Tomohiro Wierzba Konstanty Yamashita Jun-ichi Tada Yukio Yamada Yuji Fukushima Masakazu Asao Tetsuji |
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Institution: | Hanno Research Center, Taiho Pharmaceutical Co., Ltd, 1-27 Misugidai, Hanno-shi, Saitama 357-8527, Japan. syano@taiho.co.jp |
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Abstract: | 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. |
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