Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 1: Discovery of novel orally active inhibitors of human thymidine phosphorylase

• Published in: Bioorganic & medicinal chemistry 2004-07, Vol.12 (13), p.3431-3441
• Main Authors: Yano, Shingo, Kazuno, Hideki, Suzuki, Norihiko, Emura, Tomohiro, Wierzba, Konstanty, Yamashita, Jun-ichi, Tada, Yukio, Yamada, Yuji, Fukushima, Masakazu, Asao, Tetsuji
• Format: Article
• Language: English
• Subjects: 2′-Deoxy-5-(trifluoromethyl)uridine (F 3dThd); 6-Methylene-bridged uracil derivative; Absorption; Administration, Oral; Animals; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Female; General aspects; Humans; Hydrocarbons; Inhibitory Concentration 50; Macaca fascicularis; Male; Medical sciences; Methane - analogs & derivatives; Methane - chemistry; Mice; Mice, Nude; Molecular Structure; Pharmacology. Drug treatments; Stomach Neoplasms - blood; Stomach Neoplasms - drug therapy; Stomach Neoplasms - pathology; Structure-Activity Relationship; Thymidine Phosphorylase - antagonists & inhibitors; Thymidine Phosphorylase - metabolism; Thymidine phosphorylase inhibitor; TPI; Uracil - administration & dosage; Uracil - analogs & derivatives; Uracil - chemistry; Uracil - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.04.036

Discovery, synthesis, and evaluation of novel orally active human thymidine phosphorylase inhibitors are reported. 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 3dThd), 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 3dThd, 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 3dThd alone, in mice bearing human tumor xenografts. Both biochemical and pharmacological effects appeared to fit the concept as anticipated.