Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 1: discovery of novel orally active inhibitors of human thymidine phosphorylase.
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.
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
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; 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
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006838:Hydrocarbons; C030011:carbene; D014498:Uracil; D013939:Thymidine Phosphorylase; D008697:Methane