Synthesis and anti-influenza evaluation of orally active bicyclic ether derivatives related to zanamivir.
We synthesized bicyclic ether sialidase inhibitors such as tetrahydro-furan-2-yl, tetrahydro-pyran-2-yl, and oxepan-2-yl derivatives related to zanamivir. These compounds substituted by diol at the C-3' and C-4' positions resulted in the retention of low nanomolar inhibitory activities against not only influenza A virus sialidase but also influenza A virus in cell culture. Compound 11a in particular showed comparable efficacy in vivo relative to that of oseltamivir phosphate.
Masuda
Takeshi
T
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Shibuya
Satoshi
S
Arai
Masami
M
Yoshida
Shuku
S
Tomozawa
Takanori
T
Ohno
Akiko
A
Yamashita
Makoto
M
Honda
Takeshi
T
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004987:Ethers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006146:Guanidines; D009980:Influenza A virus / Q000187:drug effects / Q000201:enzymology; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*; D011714:Pyrans; D012794:Sialic Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D053243:Zanamivir
D000998:Antiviral Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D004987:Ethers; D006146:Guanidines; D011714:Pyrans; D012794:Sialic Acids; D009439:Neuraminidase; D053243:Zanamivir