title: Structure-activity relationship of purine ribonucleosides for inhibition of hepatitis C virus RNA-dependent RNA polymerase.
abstract: As part of a continued effort to identify inhibitors of hepatitis C viral (HCV) replication, we report here the synthesis and evaluation of a series of nucleoside analogues and their corresponding triphosphates. Nucleosides were evaluated for their ability to inhibit HCV RNA replication in a cell-based, subgenomic replicon system, while nucleoside triphosphates were evaluated for their ability to inhibit in vitro RNA synthesis mediated by the HCV RNA-dependent RNA polymerase, NS5B. 2'-C-Methyladenosine and 2'-C-methylguanosine were identified as potent inhibitors of HCV RNA replication, and the corresponding triphosphates were found to be potent inhibitors of HCV NS5B-mediated RNA synthesis. The data generated in the cell-based assay demonstrated a fairly stringent structure-activity relationship around the active nucleosides. Increase in steric bulk beyond methyl on C2, change in the stereo- or regiochemistry of the methyl substituent, or change of identity of the heterobase beyond that of the endogenous adenine or guanine was found to lead to loss of inhibitory activity. The results highlight the importance of the ribo configuration 2'- and 3'-hydroxy pharmacophores for inhibition of HCV RNA replication in the cell-based assay and demonstrate that inclusion of the 2'-C-methylribonucleoside pharmacophore leads to increased resistance to adenosine deaminase and purine nucleoside phosphorylase mediated metabolism.
authors.affiliation: Department of Medicinal Chemistry, Isis Pharmaceuticals, 2280 Faraday Avenue, Carlsbad, California 92008, USA. aeldrup@isisph.com
authors.forename: Anne B
authors.initials: AB
authors.lastname: Eldrup
authors.forename: Charles R
authors.initials: CR
authors.lastname: Allerson
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Sanjib
authors.initials: S
authors.lastname: Bera
authors.forename: Balkrishen
authors.initials: B
authors.lastname: Bhat
authors.forename: Neelima
authors.initials: N
authors.lastname: Bhat
authors.forename: Michele R
authors.initials: MR
authors.lastname: Bosserman
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brooks
authors.forename: Christine
authors.initials: C
authors.lastname: Burlein
authors.forename: Steven S
authors.initials: SS
authors.lastname: Carroll
authors.forename: P Dan
authors.initials: PD
authors.lastname: Cook
authors.forename: Krista L
authors.initials: KL
authors.lastname: Getty
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McMasters
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: Thazha P
authors.initials: TP
authors.lastname: Prakash
authors.forename: Marija
authors.initials: M
authors.lastname: Prhavc
authors.forename: Quanlai
authors.initials: Q
authors.lastname: Song
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Tomassini
authors.forename: Jie
authors.initials: J
authors.lastname: Xia
mesh_terms: D000243:Adenosine Deaminase / Q000737:chemistry; D016174:Hepacivirus / Q000737:chemistry*; D006860:Hydrogen Bonding; D008745:Methylation; D008968:Molecular Conformation; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D011683:Purine-Nucleoside Phosphorylase / Q000737:chemistry; D011687:Purines / Q000737:chemistry; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D012266:Ribose / Q000737:chemistry; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D011684:Purine Nucleosides; D011687:Purines; D012263:Ribonucleosides; D017361:Viral Nonstructural Proteins; D012266:Ribose; D011683:Purine-Nucleoside Phosphorylase; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; D000243:Adenosine Deaminase