4-Oxo-4,7-dihydrothieno[2,3-b]pyridines as non-nucleoside inhibitors of human cytomegalovirus and related herpesvirus polymerases

Mark E Schnute; Michele M Cudahy; Roger J Brideau; Fred L Homa; Todd A Hopkins; Mary L Knechtel; Nancee L Oien; Thomas W Pitts; Roger A Poorman; Michael W Wathen; Janet L Wieber

doi:10.1021/jm050162b

4-Oxo-4,7-dihydrothieno[2,3-b]pyridines as non-nucleoside inhibitors of human cytomegalovirus and related herpesvirus polymerases

J Med Chem. 2005 Sep 8;48(18):5794-804. doi: 10.1021/jm050162b.

Authors

Mark E Schnute¹, Michele M Cudahy, Roger J Brideau, Fred L Homa, Todd A Hopkins, Mary L Knechtel, Nancee L Oien, Thomas W Pitts, Roger A Poorman, Michael W Wathen, Janet L Wieber

Affiliation

¹ Medicinal Chemistry and Infectious Diseases Biology, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, Michigan 49001, USA. mark.e.schnute@ pfizer.com

PMID: 16134946
DOI: 10.1021/jm050162b

Abstract

A novel series of 4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamides have been identified as potential antivirals against human herpesvirus infections resulting from human cytomegalovirus (HCMV), herpes simplex virus type 1 (HSV-1), and varicella-zoster virus (VZV). Compounds 10c and 14 demonstrated broad-spectrum inhibition of the herpesvirus polymerases HCMV, HSV-1, and VZV. High specificity for the viral polymerases was observed compared to human alpha polymerase. The antiviral activity of 10c and 14, as determined by plaque reduction assay, was comparable or superior to that of existing antiherpes drugs, ganciclovir (for HCMV) and acyclovir (for HSV-1 and VZV). Drug resistance to compound 14 correlated to point mutations in conserved domain III of the herpesvirus DNA polymerase, but these mutations do not confer resistance to existing nucleoside therapy. In addition, compound 14 maintained potent antiviral activity against acyclovir-resistant HSV-1 strains. Substitution to the pyridone nitrogen (N7) was found to be critical for enhanced in vitro antiviral activity.

MeSH terms

Animals
Antiviral Agents / chemical synthesis*
Antiviral Agents / chemistry
Antiviral Agents / pharmacology
Cell Line
Cell Survival
Chlorocebus aethiops
Cytomegalovirus / drug effects*
Cytomegalovirus / enzymology
DNA-Directed DNA Polymerase / chemistry
DNA-Directed DNA Polymerase / genetics
Drug Resistance, Viral
Exodeoxyribonucleases / antagonists & inhibitors
Exodeoxyribonucleases / genetics
Herpesvirus 1, Human / drug effects*
Herpesvirus 1, Human / enzymology
Herpesvirus 3, Human / drug effects*
Herpesvirus 3, Human / enzymology
Humans
Nucleic Acid Synthesis Inhibitors*
Point Mutation
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacology
Pyridones / chemical synthesis*
Pyridones / chemistry
Pyridones / pharmacology
Structure-Activity Relationship
Thiophenes / chemical synthesis*
Thiophenes / chemistry
Thiophenes / pharmacology
Viral Plaque Assay
Viral Proteins / antagonists & inhibitors
Viral Proteins / genetics

Substances

Antiviral Agents
N-(4-chlorobenzyl)-2-(3-hydroxypropyl)-7-methyl-4-oxo-4,7-dihydrothieno(2,3-b)pyridine-5-carboxamide
N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-oxo-4,7-dihydrothieno(2,3-b)pyridine-5-carboxamide
Nucleic Acid Synthesis Inhibitors
Pyridines
Pyridones
Thiophenes
Viral Proteins
DNA-Directed DNA Polymerase
Exodeoxyribonucleases
DNA polymerase, Simplexvirus