Discovery of Potent, Orally Bioavailable Inhibitors of Human Cytomegalovirus.
ACS Med Chem Lett
; 7(5): 525-30, 2016 May 12.
Article
en En
| MEDLINE
| ID: mdl-27190604
ABSTRACT
A high-throughput screen based on a viral replication assay was used to identify inhibitors of the human cytomegalovirus. Using this approach, hit compound 1 was identified as a 4 µM inhibitor of HCMV that was specific and selective over other herpes viruses. Time of addition studies indicated compound 1 exerted its antiviral effect early in the viral life cycle. Mechanism of action studies also revealed that this series inhibited infection of MRC-5 and ARPE19 cells by free virus and via direct cell-to-cell spread from infected to uninfected cells. Preliminary structure-activity relationships demonstrated that the potency of compound 1 could be improved to a low nanomolar level, but metabolic stability was a key optimization parameter for this series. A strategy focused on minimizing metabolic hydrolysis of the N1-amide led to an alternative scaffold in this series with improved metabolic stability and good pharmacokinetic parameters in rat.
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1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
ACS Med Chem Lett
Año:
2016
Tipo del documento:
Article
País de afiliación:
Canadá