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Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 2: optimization of inhibitors of human thymidine phosphorylase and their selectivity with uridine phosphorylase.

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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Yano S,Kazuno H,Sato T,Suzuki N,Emura T,Wierzba K,Yamashita J,Tada Y,Yamada Y,Fukushima M,Asao T

doi

10.1016/j.bmc.2004.04.046

subject

Has Abstract

pub_date

2004-07-01 00:00:00

pages

3443-50

issue

13

eissn

0968-0896

issn

1464-3391

pii

S0968089604003396

journal_volume

12

pub_type

杂志文章

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