RESUMO
We identified a novel class of 4-oxo-dihydroquinolines represented by PNU-183792 which specifically inhibit herpesvirus polymerases. PNU-183792 was highly active against human cytomegalovirus (HCMV, IC(50) value 0.69 microM), varicella zoster virus (VZV, IC(50) value 0.37 microM) and herpes simplex virus (HSV, IC(50) value 0.58 microM) polymerases but was inactive (IC(50) value >40 microM) against human alpha (alpha), gamma (gamma), or delta (delta) polymerases. In vitro antiviral activity against HCMV was determined using cytopathic effect, plaque reduction and virus yield reduction assays (IC(50) ranging from 0.3 to 2.4 microM). PNU-183792 antiviral activity against both VZV (IC(50) value 0.1 microM) and HSV (IC(50) ranging from 3 to 5 microM) was analyzed using plaque reduction assays. PNU-183792 was also active (IC(50) ranging 0.1-0.7 microM) in cell culture assays against simian varicella virus (SVV), murine cytomegalovirus (MCMV) and rat cytomegalovirus (RCMV). Cell culture activity was compared with the appropriate licensed drugs ganciclovir (GCV), cidofovir (CDV) and acyclovir (ACV). PNU-183792 was also active against both GCV-resistant and CDV-resistant HCMV and against ACV-resistant HSV. Toxicity assays using four different species of proliferating mammalian cells indicated PNU-183792 was not cytotoxic at relevant drug concentrations (CC(50) value >100 microM). PNU-183792 was inactive against unrelated DNA and RNA viruses indicating specificity for herpesviruses. In animals, PNU-183792 was orally bioavailable and was efficacious in a model of lethal MCMV infection.
Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Infecções por Herpesviridae/tratamento farmacológico , Herpesviridae/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico , Quinolinas/farmacologia , Animais , Antivirais/química , Antivirais/farmacocinética , Linhagem Celular , Farmacorresistência Viral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Herpesviridae/enzimologia , Infecções por Herpesviridae/virologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Muromegalovirus/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
Despite investment in programs to manage the development of resistance to existing agents, this continues to drive the need for discovery of novel antiparasitic agents for veterinary medicine. Historically, antiparasitic drug discovery was driven by empirical screening, but technological advances have lead to an increased focus on mechanism-based approaches to drug discovery and this is projected to increase as our capabilities advance to improve both the throughput of assays and the quality of data generated. Investment in the development of combination products with novel agents is increasing and, despite regulatory hurdles in some regions, efforts to globally harmonize regulations will aid in delivering safe, efficacious drugs to help in resistance management and integrated parasite control programs.
Assuntos
Antiparasitários/química , Descoberta de Drogas/tendências , Drogas Veterinárias/química , Aminoacetonitrila/química , Aminoacetonitrila/farmacocinética , Animais , Antiparasitários/farmacocinética , Combinação de Medicamentos , Macrolídeos/química , Macrolídeos/farmacocinética , Oxazinas/química , Oxazinas/farmacocinética , Semicarbazonas/química , Semicarbazonas/farmacocinética , Drogas Veterinárias/farmacocinéticaRESUMO
A novel series of 2-aryl-2-hydroxyethylamine substituted 4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamides have been identified as potent antivirals against human herpesviruses. These compounds demonstrate broad-spectrum inhibition of the herpesvirus polymerases HCMV, HSV-1, EBV, and VZV with high specificity compared to human DNA polymerases.
Assuntos
Antivirais/farmacologia , Citomegalovirus/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Etilaminas/farmacologia , Exodesoxirribonucleases/antagonistas & inibidores , Herpesviridae/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 4/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico , Piridinas/farmacologia , Proteínas Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/uso terapêutico , Ligação Competitiva , DNA Polimerase Dirigida por DNA , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Etilaminas/síntese química , Herpes Zoster/tratamento farmacológico , Herpesviridae/enzimologia , Humanos , Modelos Químicos , Piridinas/síntese química , Relação Estrutura-AtividadeRESUMO
The susceptibility of human cytomegalovirus (CMV) and varicella zoster virus (VZV) clinical isolates to PNU-183792, a 4-oxo-dihydroquinoline, was examined. The antiviral potency of PNU-183792, a non-nucleoside inhibitor, was compared to the licensed nucleoside inhibitors ganciclovir and acyclovir using plaque reduction and virus yield reduction assays. PNU-183792 was as potent against CMV as ganciclovir and was superior in potency to acyclovir against VZV. PNU-183792 represents a new class of non-nucleoside inhibitors of human herpesviruses.