Synthesis and HCV inhibitory properties of 9-deaza- and 7,9-dideaza-7-oxa-2'-C-methyladenosine.
As a part of an ongoing medicinal chemistry effort to identify inhibitors of the Hepatitis C Virus RNA replication, we report here the synthesis and biological evaluation of 9-deaza- and 7,9-dideaza-7-oxa-2'-C-methyladenosine. The parent 2'-C-methyladenosine shows excellent intracellular inhibitory activity but poor pharmacokinetic profile. Replacement of the nucleoside-defining 9-N of 2'-C-methyladenosine with a carbon atom was designed to yield metabolically more stable C-nucleosides. Modifications at position 7 were designed to exploit the importance of the hydrogen bond accepting properties of this heteroatom in modulating the adenosine deaminase (ADA) mediated 6-N deamination. 7-Oxa-7,9-dideaza-2'-C-methyladenosine was found to be a moderately active inhibitor of intracellular HCV RNA replication, whereas 9-deaza- 2'-C-methyladenosine showed only weak activity despite excellent overlap of both of the synthesized target compounds with 2'-C-methyladenosine's three dimensional structure. Position 7 of the nucleobase proved to be an effective handle for modulating ADA-mediated degradation, with the rate of degradation correlating with the hydrogen-bonding properties at this position.
Butora
Gabor
G
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. gabor_butora@merck.com
Olsen
David B
DB
Carroll
Steven S
SS
McMasters
Daniel R
DR
Schmitt
Christoph
C
Leone
Joseph F
JF
Stahlhut
Mark
M
Burlein
Christine
C
Maccoss
Malcolm
M
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D012367:RNA, Viral / Q000378:metabolism; D014779:Virus Replication
C522378:7,9-dideaza-7-oxa-2'-C-methyladenosine; D000998:Antiviral Agents; D012367:RNA, Viral; D000241:Adenosine