RESUMO
A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.
Assuntos
Antineoplásicos/síntese química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Pirazóis/síntese química , Pirimidinas/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Ligação Competitiva , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Transplante de Neoplasias , Ligação Proteica , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
The HCV RNA-dependent RNA polymerase has emerged as one of the key targets for novel anti-HCV therapy development. Herein, we report the optimization of the dihydropyrone series inhibitors to improve compound aqueous solubility and reduce CYP2D6 inhibition, which led to the discovery of compound 24 (PF-00868554). Compound 24 is a potent and selective HCV polymerase inhibitor with a favorable pharmacokinetic profile and has recently entered a phase II clinical evaluation in patients with genotype 1 HCV.
Assuntos
Antivirais/síntese química , Hepacivirus/enzimologia , Pironas/síntese química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Triazóis/síntese química , Administração Oral , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Cristalografia por Raios X , Inibidores do Citocromo P-450 CYP2D6 , Cães , Macaca fascicularis , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Pironas/farmacocinética , Pironas/farmacologia , Ratos , Ratos Sprague-Dawley , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/farmacocinética , Triazóis/farmacologiaRESUMO
The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure-activity relationship (SAR) studies led to the identification of compounds, exemplified by 23 and 24, with significantly improved antiviral activities in the cell-based replicon assay and favorable pharmacokinetic profiles.
Assuntos
Antivirais/síntese química , Hepacivirus/enzimologia , Pironas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Regulação Alostérica , Animais , Antivirais/química , Antivirais/farmacologia , Disponibilidade Biológica , Células CACO-2 , Linhagem Celular Tumoral , Meia-Vida , Humanos , Permeabilidade , Pironas/química , Pironas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/genéticaRESUMO
A novel class of non-nucleoside HCV NS5B polymerase inhibitors has been identified from screening. A co-crystal structure revealed an allosteric binding site in the protein that required a unique conformational change to accommodate inhibitor binding. Herein we report the structure-activity relationships (SARs) of this novel class of dihydropyrone-containing compounds that show potent inhibitory activities against the HCV RNA polymerase in biochemical assays.