title: Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 1: discovery of novel orally active inhibitors of human thymidine phosphorylase.
abstract: A series of novel 6-methylene-bridged uracil derivatives have been prepared as inhibitors of human thymidine phosphorylase (TP). To enhance the in vivo antitumor activity of fluorinated pyrimidine 2'-deoxyribonucleosides such as 2'-deoxy-5-(trifluoromethyl)uridine (F(3)dThd), a potent TP inhibitor preventing their degradation to an inactive compound, has become a target of medicinal chemistry. We present here the synthesis and evaluation of novel human TP inhibitors. Introduction of an N-substituted aminomethyl side chain at the 6-position of 5-chlorouracil has improved water solubility and enhanced inhibitory activity compared with the known TP inhibitor, 6-amino-5-chlorouracil. Compound 42 was reasonably well absorbed in mice after oral administration. When combined with F(3)dThd, compound 42 exerted its TP inhibitory potency by increasing the maximum plasma concentrations of the former as evidenced in experiments with monkeys. Positive changes in pharmacokinetic profile were accompanied by the enhanced in vivo antitumor activity of this combination when compared to F(3)dThd alone, in mice bearing human tumor xenografts. Both biochemical and pharmacological effects appeared to fit the concept as anticipated.
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: 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; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006838:Hydrocarbons; D020128:Inhibitory Concentration 50; D008252:Macaca fascicularis; D008297:Male; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006838:Hydrocarbons; C030011:carbene; D014498:Uracil; D013939:Thymidine Phosphorylase; D008697:Methane