1,2,3-Triazole-containing uracil derivatives with excellent pharmacokinetics as a novel class of potent human deoxyuridine triphosphatase inhibitors.
Deoxyuridine triphosphatase (dUTPase) has emerged as a potential target for drug development as a 5-fluorouracil-based combination chemotherapy. We describe the design and synthesis of a novel class of human dUTPase inhibitors, 1,2,3-triazole-containing uracil derivatives. Compound 45a, which possesses 1,5-disubstituted 1,2,3-triazole moiety that mimics the amide bond of tert-amide-containing inhibitor 6b locked in a cis conformation showed potent inhibitory activity, and its structure-activity relationship studies led us to the discovery of highly potent inhibitors 48c and 50c (IC(50) = ~0.029 μM). These derivatives dramatically enhanced the growth inhibition activity of 5-fluoro-2'-deoxyuridine against HeLa S3 cells in vitro (EC(50) = ~0.05 μM). In addition, compound 50c exhibited a markedly improved pharmacokinetic profile as a result of the introduction of a benzylic hydroxy group and significantly enhanced the antitumor activity of 5-fluorouracil against human breast cancer MX-1 xenograft model in mice. These data indicate that 50c is a promising candidate for combination cancer chemotherapies with TS inhibitors.
Drug Discovery Research Center, Taiho Pharmaceutical Co. Ltd., Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
Hitoshi
H
Miyakoshi
Seiji
S
Miyahara
Tatsushi
T
Yokogawa
Kanji
K
Endoh
Toshiharu
T
Muto
Wakako
W
Yano
Takeshi
T
Wakasa
Hiroyuki
H
Ueno
Khoon Tee
KT
Chong
Junko
J
Taguchi
Makoto
M
Nomura
Yayoi
Y
Takao
Akio
A
Fujioka
Akihiro
A
Hashimoto
Kenjirou
K
Itou
Keisuke
K
Yamamura
Satoshi
S
Shuto
Hideko
H
Nagasawa
Masayoshi
M
Fukuoka
D000577:Amides / Q000737:chemistry; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014498:Uracil / Q000737:chemistry*
D000577:Amides; D004791:Enzyme Inhibitors; D014230:Triazoles; D014498:Uracil; D013940:Thymidylate Synthase; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase