title: Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza.
abstract: The synthesis, antiviral and pharmacokinetic properties of zanamivir (ZMV) dimers 8 and 13 are described. The compounds are highly potent neuraminidase (NA) inhibitors which, along with dimer 3, are being investigated as potential second generation inhaled therapies both for the treatment of influenza and for prophylactic use. They show outstanding activity in a 1 week mouse influenza prophylaxis assay, and compared with ZMV, high concentrations of 8 and 13 are found in rat lung tissue after 1 week. Retention of compounds in rat lung tissue correlated both with molecular weight (excluding 3 and 15) and with a capacity factor K' derived from immobilized artificial membrane (IAM) chromatography (including 3 and 15). Pharmacokinetic parameters for 3, 8 and 13 in rats show the compounds have short to moderate plasma half-lives, low clearances and low volumes of distribution. Dimer 3 shows NA inhibitory activity against N1 viruses including the recent highly pathogenic H5N1 A/Chicken/Vietnam/8/2004. In plaque reduction assays, 3, 8 and 13 show good to outstanding potency against a panel of nine flu A and B virus strains. Consistent with its shorter and more rigid linking group, dimer 8 has been successfully crystallized.
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom. simon.jf.macdonald@gsk.com
authors.forename: Simon J F
authors.initials: SJ
authors.lastname: Macdonald
authors.forename: Rachel
authors.initials: R
authors.lastname: Cameron
authors.forename: Derek A
authors.initials: DA
authors.lastname: Demaine
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Fenton
authors.forename: Graham
authors.initials: G
authors.lastname: Foster
authors.forename: David
authors.initials: D
authors.lastname: Gower
authors.forename: J Nicole
authors.initials: JN
authors.lastname: Hamblin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hamilton
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Hart
authors.forename: Alan P
authors.initials: AP
authors.lastname: Hill
authors.forename: Graham G A
authors.initials: GG
authors.lastname: Inglis
authors.forename: Betty
authors.initials: B
authors.lastname: Jin
authors.forename: Haydn T
authors.initials: HT
authors.lastname: Jones
authors.forename: Darryl B
authors.initials: DB
authors.lastname: McConnell
authors.forename: Jennifer
authors.initials: J
authors.lastname: McKimm-Breschkin
authors.forename: Gail
authors.initials: G
authors.lastname: Mills
authors.forename: Van
authors.initials: V
authors.lastname: Nguyen
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Owens
authors.forename: Nigel
authors.initials: N
authors.lastname: Parry
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Shanahan
authors.forename: Donna
authors.initials: D
authors.lastname: Smith
authors.forename: Keith G
authors.initials: KG
authors.lastname: Watson
authors.forename: Wen-Yang
authors.initials: WY
authors.lastname: Wu
authors.forename: Simon P
authors.initials: SP
authors.lastname: Tucker
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D003460:Crystallization; D019281:Dimerization; D006146:Guanidines; D053124:Influenza A Virus, H5N1 Subtype; D009980:Influenza A virus / Q000187:drug effects* / Q000201:enzymology; D009981:Influenza B virus / Q000187:drug effects* / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D008297:Male; D008567:Membranes, Artificial; D051379:Mice; D008958:Models, Molecular; D008970:Molecular Weight; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009976:Orthomyxoviridae Infections / Q000517:prevention & control* / Q000821:virology; D011714:Pyrans; D051381:Rats; D017207:Rats, Sprague-Dawley; D012794:Sialic Acids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D010948:Viral Plaque Assay; D053243:Zanamivir
chemical_list: C500625:4,4'-bis(4'-(((((1-(3-(acetylamino)-4-((amino(imino)methyl)amino)-6-carboxy-3,4-dihydro-2H-pyran-2-yl)-2,3-dihydroxypropyl)oxy)carbonyl)amino)methyl))biphenyl; D000998:Antiviral Agents; D006146:Guanidines; D008567:Membranes, Artificial; D011714:Pyrans; D012794:Sialic Acids; C500626:zanamivir dimer2; D009439:Neuraminidase; D053243:Zanamivir