Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza.
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.
Macdonald
Simon J F
SJ
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom. simon.jf.macdonald@gsk.com
Cameron
Rachel
R
Demaine
Derek A
DA
Fenton
Rob J
RJ
Foster
Graham
G
Gower
David
D
Hamblin
J Nicole
JN
Hamilton
Stephanie
S
Hart
Graham J
GJ
Hill
Alan P
AP
Inglis
Graham G A
GG
Jin
Betty
B
Jones
Haydn T
HT
McConnell
Darryl B
DB
McKimm-Breschkin
Jennifer
J
Mills
Gail
G
Nguyen
Van
V
Owens
Ian J
IJ
Parry
Nigel
N
Shanahan
Stephen E
SE
Smith
Donna
D
Watson
Keith G
KG
Wu
Wen-Yang
WY
Tucker
Simon P
SP
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
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