Format

Send to

Choose Destination
Bioorg Med Chem. 2012 Aug 1;20(15):4801-11. doi: 10.1016/j.bmc.2012.05.067. Epub 2012 Jun 6.

Synthesis and antiviral properties of novel 7-heterocyclic substituted 7-deaza-adenine nucleoside inhibitors of Hepatitis C NS5B polymerase.

Author information

1
Istituto di Ricerche di Biologia Molecolare P. Angeletti S.p.A., Merck Research Laboratories Rome, Via Pontina Km 30,600, 00040 Pomezia, Italy. medifrancesco@mdanderson.org

Abstract

Previous investigations in our laboratories resulted in the discovery of a novel series of potent nucleoside inhibitors of Hepatitis C virus (HCV) NS5B polymerase bearing tetracyclic 7-substituted 7-deaza-adenine nucleobases. The planarity of such modified systems was suggested to play a role in the high inhibitory potency observed. This paper describes how we envisaged to maintain the desired planarity of the modified nucleobase by means of an intra-molecular H-bond, engaging a H-bond donor atom on an appropriately substituted 7-heterocyclic residue with the adjacent amino group of the nucleobase. The success of this strategy is reflected by the identification of several novel potent nucleoside inhibitors of HCV NS5B bearing a 7-heterocyclic substituted 7-deaza-adenine nucleobase. Amongst these, the 1,2,4-oxadiazole analog 11 showed high antiviral potency against HCV replication in replicon cells and efficient conversion to the corresponding NTP in vivo, with high and sustained levels of NTP measured in rat liver following intravenous and oral administration.

PMID:
22770556
DOI:
10.1016/j.bmc.2012.05.067
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center