Synthesis and evaluation of a series of 2'-deoxy analogues of the antiviral agent 5,6-dichloro-2-isopropylamino-1-(beta-L-ribofuranosyl)-1H-benzimidazole (1263W94).
A series of 2'-deoxy analogues of the antiviral agent 5,6-dichloro-2-isopropylamino-1-(beta-L-ribofuranosyl)-1H-benzimidazole (1263W94) were synthesized and evaluated for activity against human cytomegalovirus (HCMV) and for cytotoxicity. The 2-substituents in the benzimidazole moiety correspond to those that were used in the 1263W94 series. In general, as was found in the 1263W94 series, cyclic and branched alkylamino groups were needed for potent activity against HCMV. Three analogues 3a, 3b and 3d were as potent as 1263W94. Further evaluation of two analogues, 3a and 3b, suggested that these 2'-deoxy analogues may act via a novel mechanism of action similar to that of 1263W94. These 2'-deoxy analogues generally lacked cytotoxicity in vitro. Pharmacokinetic parameters in mice and protein binding properties of 3a were quite similar to 1263W94. However, the oral bioavailability of 3a was only half of that observed for 1263W94.
Chan
J H
JH
Division of Chemistry, Glaxo Wellcome Inc., Research Triangle Park, NC 27709, USA.
Chamberlain
S D
SD
Biron
K K
KK
Davis
M G
MG
Harvey
R J
RJ
Selleseth
D W
DW
Dornsife
R E
RE
Dark
E H
EH
Frick
L W
LW
Townsend
L B
LB
Drach
J C
JC
Koszalka
G W
GW
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004004:Dichlororibofuranosylbenzimidazole / Q000031:analogs & derivatives
D000998:Antiviral Agents; D001562:Benzimidazoles; D012263:Ribonucleosides; C400401:maribavir; D004004:Dichlororibofuranosylbenzimidazole