Discovery of a 2'-fluoro-2'-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties

Thorsten A Kirschberg; Sammy Metobo; Michael O Clarke; Vangelis Aktoudianakis; Darius Babusis; Ona Barauskas; Gabriel Birkus; Thomas Butler; Daniel Byun; Gregory Chin; Edward Doerffler; Thomas E Edwards; Martijn Fenaux; Rick Lee; Willard Lew; Michael R Mish; Eisuke Murakami; Yeojin Park; Neil H Squires; Neeraj Tirunagari; Ting Wang; Mark Whitcomb; Jie Xu; Huiling Yang; Hong Ye; Lijun Zhang; Todd C Appleby; Joy Y Feng; Adrian S Ray; Aesop Cho; Choung U Kim

doi:10.1016/j.bmcl.2017.02.037

Discovery of a 2'-fluoro-2'-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties

Bioorg Med Chem Lett. 2017 Apr 15;27(8):1840-1847. doi: 10.1016/j.bmcl.2017.02.037. Epub 2017 Feb 20.

Authors

Thorsten A Kirschberg¹, Sammy Metobo², Michael O Clarke², Vangelis Aktoudianakis², Darius Babusis², Ona Barauskas², Gabriel Birkus², Thomas Butler², Daniel Byun², Gregory Chin², Edward Doerffler², Thomas E Edwards³, Martijn Fenaux², Rick Lee², Willard Lew², Michael R Mish², Eisuke Murakami², Yeojin Park², Neil H Squires², Neeraj Tirunagari², Ting Wang², Mark Whitcomb², Jie Xu², Huiling Yang², Hong Ye², Lijun Zhang², Todd C Appleby², Joy Y Feng², Adrian S Ray², Aesop Cho², Choung U Kim²

Affiliations

¹ Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. Electronic address: tkirschberg@gilead.com.
² Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
³ Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.

PMID: 28274633
DOI: 10.1016/j.bmcl.2017.02.037

Abstract

A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.

Keywords: Antiviral; C-nucleoside; Hepatitis C; NS5B polymerase.

MeSH terms

Amides / chemistry
Amides / pharmacokinetics
Amides / pharmacology
Animals
Antiviral Agents / chemistry*
Antiviral Agents / pharmacokinetics
Antiviral Agents / pharmacology*
Caco-2 Cells
Cell Line
Cricetinae
Drug Discovery
Drug Resistance, Viral
Halogenation
Hepacivirus / drug effects*
Hepacivirus / genetics
Hepacivirus / physiology
Hepatitis C / drug therapy
Humans
Methylation
Molecular Docking Simulation
Nucleosides / chemistry*
Nucleosides / pharmacokinetics
Nucleosides / pharmacology*
Phosphoric Acids / chemistry
Phosphoric Acids / pharmacokinetics
Phosphoric Acids / pharmacology
Point Mutation
Prodrugs / chemistry
Prodrugs / pharmacokinetics
Prodrugs / pharmacology
Viral Nonstructural Proteins / antagonists & inhibitors*
Viral Nonstructural Proteins / genetics
Viral Nonstructural Proteins / metabolism
Virus Replication / drug effects

Substances

Amides
Antiviral Agents
Nucleosides
Phosphoric Acids
Prodrugs
Viral Nonstructural Proteins
phosphoramidic acid
NS-5 protein, hepatitis C virus