Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 2: optimization of inhibitors of human thymidine phosphorylase and their selectivity with uridine phosphorylase.
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.
Yano
Shingo
S
Hanno Research Center, Taiho Pharmaceutical Co., Ltd, 1-27 Misugidai, Hanno-shi, Saitama 357-8527, Japan. syano@taiho.co.jp
Kazuno
Hideki
H
Sato
Tsutomu
T
Suzuki
Norihiko
N
Emura
Tomohiro
T
Wierzba
Konstanty
K
Yamashita
Jun-ichi
J
Tada
Yukio
Y
Yamada
Yuji
Y
Fukushima
Masakazu
M
Asao
Tetsuji
T
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006838:Hydrocarbons; D020128:Inhibitory Concentration 50; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry*; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D006838:Hydrocarbons; C030011:carbene; D014498:Uracil; D014543:Uridine Phosphorylase; D013939:Thymidine Phosphorylase; D008697:Methane