| Literature DB >> 15186830 |
Shingo Yano1, Hideki Kazuno, Tsutomu Sato, Norihiko Suzuki, Tomohiro Emura, Konstanty Wierzba, Jun-ichi Yamashita, Yukio Tada, Yuji Yamada, Masakazu Fukushima, Tetsuji Asao.
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.Entities:
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Year: 2004 PMID： 15186830 DOI： 10.1016/j.bmc.2004.04.046
Source DB: PubMed Journal: Bioorg Med Chem ISSN： 0968-0896 Impact factor: 3.641