Concise syntheses and HCV NS5B polymerase inhibition of (2'R)-3 and (2'S)-2'-ethynyluridine-10 and related nucleosides

Frank Bennett; Alexei V Buevich; Hsueh-Cheng Huang; Vinay Girijavallabhan; Angela D Kerekes; Yuhua Huang; Asra Malikzay; Elizabeth Smith; Eric Ferrari; Mary Senior; Rebecca Osterman; Lingyan Wang; Jun Wang; Haiyan Pu; Quang T Truong; Paul Tawa; Stephane L Bogen; Ian W Davies; Ann E Weber

doi:10.1016/j.bmcl.2017.06.064

Concise syntheses and HCV NS5B polymerase inhibition of (2'R)-3 and (2'S)-2'-ethynyluridine-10 and related nucleosides

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5349-5352. doi: 10.1016/j.bmcl.2017.06.064. Epub 2017 Jun 24.

Authors

Frank Bennett¹, Alexei V Buevich², Hsueh-Cheng Huang³, Vinay Girijavallabhan⁴, Angela D Kerekes⁴, Yuhua Huang⁴, Asra Malikzay⁵, Elizabeth Smith⁵, Eric Ferrari⁵, Mary Senior⁶, Rebecca Osterman⁶, Lingyan Wang⁴, Jun Wang⁴, Haiyan Pu⁴, Quang T Truong⁴, Paul Tawa⁵, Stephane L Bogen⁴, Ian W Davies⁴, Ann E Weber⁴

Affiliations

¹ Merck & Co., Inc., MRL., Department of Medicinal Chemistry, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. Electronic address: frank.bennett@merck.com.
² Merck & Co., Inc., MRL., Department of Structure Elucidation, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. Electronic address: alexei.buevich@merck.com.
³ Merck & Co., Inc., MRL., Department of Viirology, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. Electronic address: hseu-cheng.huang@merck.com.
⁴ Merck & Co., Inc., MRL., Department of Medicinal Chemistry, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
⁵ Merck & Co., Inc., MRL., Department of Viirology, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
⁶ Merck & Co., Inc., MRL., Department of Structure Elucidation, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.

PMID: 29056248
DOI: 10.1016/j.bmcl.2017.06.064

Abstract

(2'R)-Ethynyl uridine 3, and its (2'S)-diastereomer 10, are synthesised in a divergent fashion from the inexpensive parent nucleoside. Both nucleoside analogues are obtained from a total of 5 simple synthetic steps and 3 trivial column chromatography purifications. To evaluate their effectiveness against HCV NS5B polymerase, the nucleosides were converted to their respective 5'-O-triphosphates. Subsequently, this lead to the discovery of the 2'-β-ethynyl 18 and -propynyl 20 nucleotides having significantly improved potency over Sofosbuvir triphosphate 24.

Keywords: Cancer; Hepatitis; Nucleoside.

MeSH terms

Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Dose-Response Relationship, Drug
Hepacivirus / drug effects*
Microbial Sensitivity Tests
Molecular Conformation
Nucleosides / chemical synthesis
Nucleosides / chemistry
Nucleosides / pharmacology*
Structure-Activity Relationship
Uridine / analogs & derivatives
Uridine / chemistry
Uridine / pharmacology*
Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

Antiviral Agents
Nucleosides
Viral Nonstructural Proteins
NS-5 protein, hepatitis C virus
Uridine