Synthesis and Anti-influenza Evaluation of Polyvalent Sialidase Inhibitors Bearing 4-Guanidino-Neu5Ac2en Derivatives

• Published in: Chemical & Pharmaceutical Bulletin Vol. 51; no. 12; pp. 1386 - 1398
• Main Authors: Masuda, Takeshi, Yoshida, Shuku, Arai, Masami, Kaneko, Satoru, Yamashita, Makoto, Honda, Takeshi
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.12.2003; Pharmaceutical Society of Japan; Pharmaceutical Soc Japan; Maruzen; Japan Science and Technology Agency
• Subjects: Administration, Intranasal; Animals; anti-influenza drug; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - administration & dosage; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical - methods; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Female; Guanidines; Influenza A virus - drug effects; Influenza A virus - growth & development; Life Sciences & Biomedicine; Medical sciences; Mice; Mice, Inbred BALB C; Neuraminidase - antagonists & inhibitors; Neuraminidase - metabolism; Orthomyxoviridae Infections - drug therapy; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; poly-L-glutamine; Pyrans; Science & Technology; sialic acid; Sialic Acids - administration & dosage; Sialic Acids - chemistry; Sialic Acids - pharmacology; sialidase inhibitor; Zanamivir; sialidase inhibitor; NEU5AC2EN; DESIGN; ENTRY; GG167 4-GUANIDINO-2,4-DIDEOXY-2,3-DEHYDRO-N-ACETYLNEURAMINIC ACID; L-GLUTAMIC ACID; NEURAMINIDASE; PHARMACOKINETICS; sialic acid; poly-L-glutamine; anti-influenza drug; INFLUENZA-VIRUS REPLICATION; zanamivir; Sialic acid; Orthomyxoviridae; Drug carrier; poly-i -glutamine; Zanamivir; Structure activity relation; Antiviral; Chemical synthesis; Glutamic acid derivative polymer; Ether; Enzyme; Control release polymer; Rodentia; Enzyme inhibitor; Guanidines; In vitro; Aminoacid polymer; Virus; In vivo; Vertebrata; Chemical modification; Influenzavirus A; Mammalia; Mouse; Influenza A virus; Glycosidases; Analog; Animal; Exo-α-sialidase; Hydrolases; O-Glycosidases; Ethylenic compound
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.51.1386

Polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives on a poly-L-glutamine backbone are described. Aiming for a longer retention time of 4-guanidino-Neu5Ac2en (zanamivir) in bronchi and lungs, we focused on supermolecules bearing 4-guanidino-Neu5Ac2en derivatives bound at their C-7 position through noncleavable alkyl ether linkages. We first found that alkylation of the 7-hydroxyl group of sialic acid derivative 8 proceeded smoothly, and produced 7-O-alkyl-4-guanidino-Neu5Ac2en derivatives 13, which exhibited equipotent inhibitory activity against not only influenza A virus sialidase but also influenza A virus in the cell culture. Next, we synthesized poly-L-glutamine bearing 7-O-alkyl-4-guanidino-Neu5Ac2en derivatives linked by amide bonds, 26, which showed enhanced antiviral activity against influenza A virus and more potent efficacy in vivo relative to a monomeric sialidase inhibitor.