4-Oxo-4,7-dihydrothieno[2,3-b]pyridines as non-nucleoside inhibitors of human cytomegalovirus and related herpesvirus polymerases.
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.
Schnute
Mark E
ME
Medicinal Chemistry and Infectious Diseases Biology, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, Michigan 49001, USA. mark.e.schnute@ pfizer.com
Cudahy
Michele M
MM
Brideau
Roger J
RJ
Homa
Fred L
FL
Hopkins
Todd A
TA
Knechtel
Mary L
ML
Oien
Nancee L
NL
Pitts
Thomas W
TW
Poorman
Roger A
RA
Wathen
Michael W
MW
Wieber
Janet L
JL
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus / Q000187:drug effects* / Q000201:enzymology; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics; D024882:Drug Resistance, Viral; D005090:Exodeoxyribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors; D017354:Point Mutation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics
D000998:Antiviral Agents; C504987:N-(4-chlorobenzyl)-2-(3-hydroxypropyl)-7-methyl-4-oxo-4,7-dihydrothieno(2,3-b)pyridine-5-carboxamide; C504988:N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-oxo-4,7-dihydrothieno(2,3-b)pyridine-5-carboxamide; D019384:Nucleic Acid Synthesis Inhibitors; D011725:Pyridines; D011728:Pyridones; D013876:Thiophenes; D014764:Viral Proteins; D004259:DNA-Directed DNA Polymerase; D005090:Exodeoxyribonucleases; C043417:DNA polymerase, Simplexvirus