Identification of Non-Nucleoside Inhibitors of the Respiratory Syncytial Virus Polymerase Complex.
J Med Chem
; 60(6): 2305-2325, 2017 03 23.
Article
em En
| MEDLINE
| ID: mdl-28245119
ABSTRACT
Respiratory syncytial virus (RSV) represents a threat to infants, the elderly, and the immunocompromised. RSV entry blockers are in clinical trials, but escape mutations challenge their potential. In search of RSV inhibitors, we have integrated a signature resistance mutation into a recombinant RSV virus and applied the strain to high-throughput screening. Counterscreening of candidates returned 14 confirmed hits with activities in the nano- to low-micromolar range. All blocked RSV polymerase activity in minigenome assays. Compound 1a (GRP-74915) was selected for development based on activity (EC50 = 0.21 µM, selectivity index (SI) 40) and scaffold. Resynthesis confirmed the potency of the compound, which suppressed viral RNA synthesis in infected cells. However, metabolic testing revealed a short half-life in the presence of mouse hepatocyte fractions. Metabolite tracking and chemical elaboration combined with 3D-quantitative structure-activity relationship modeling yielded analogues (i.e., 8n EC50 = 0.06 µM, SI 500) that establish a platform for the development of a therapeutic candidate.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antivirais
/
RNA Polimerases Dirigidas por DNA
/
Desenho de Fármacos
/
Vírus Sincicial Respiratório Humano
/
Infecções por Vírus Respiratório Sincicial
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos