title: 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.
authors.affiliation: Hanno Research Center, Taiho Pharmaceutical Co., Ltd, 1-27 Misugidai, Hanno-shi, Saitama 357-8527, Japan. syano@taiho.co.jp
authors.forename: Shingo
authors.initials: S
authors.lastname: Yano
authors.forename: Hideki
authors.initials: H
authors.lastname: Kazuno
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sato
authors.forename: Norihiko
authors.initials: N
authors.lastname: Suzuki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Emura
authors.forename: Konstanty
authors.initials: K
authors.lastname: Wierzba
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Yamashita
authors.forename: Yukio
authors.initials: Y
authors.lastname: Tada
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamada
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fukushima
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Asao
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D006838:Hydrocarbons; C030011:carbene; D014498:Uracil; D014543:Uridine Phosphorylase; D013939:Thymidine Phosphorylase; D008697:Methane