Linked Life Data

17521911

Source:http://linkedlifedata.com/resource/pubmed/id/17521911

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
15
pubmed:dateCreated
2007-6-12
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0968-0896
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
15
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5219-29
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Synthesis and HCV inhibitory properties of 9-deaza- and 7,9-dideaza-7-oxa-2'-C-methyladenosine.
pubmed:affiliation
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. gabor_butora@merck.com
pubmed:publicationType
Journal Article