title: Synthesis and antiviral properties of novel 7-heterocyclic substituted 7-deaza-adenine nucleoside inhibitors of Hepatitis C NS5B polymerase.
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.
authors: 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
authors: M Emilia
authors: ME
authors: Di Francesco
authors: Salvatore
authors: S
authors: Avolio
authors: Marco
authors: M
authors: Pompei
authors: Silvia
authors: S
authors: Pesci
authors: Edith
authors: E
authors: Monteagudo
authors: Vincenzo
authors: V
authors: Pucci
authors: Claudio
authors: C
authors: Giuliano
authors: Fabrizio
authors: F
authors: Fiore
authors: Michael
authors: M
authors: Rowley
authors: Vincenzo
authors: V
authors: Summa
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012093:Replicon / Q000187:drug effects; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009705:Nucleosides; D017361:Viral Nonstructural Proteins; C576633:7-deaza-adenine nucleoside; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase