Development of a New Structural Class of Broadly Acting HCV Non-Nucleoside Inhibitors Leading to the Discovery of MK-8876.
ChemMedChem
; 12(17): 1436-1448, 2017 09 07.
Article
en En
| MEDLINE
| ID: mdl-28741898
ABSTRACT
Studies directed at developing a broadly acting non-nucleoside inhibitor of HCV NS5B led to the discovery of a novel structural class of 5-aryl benzofurans that simultaneously interact with both the palmâ
I and palmâ
II binding regions. An initial candidate was potent inâ
vitro against HCV GT1a and GT1b replicons, and induced multi-log reductions in HCV viral load when orally dosed to chronic GT1 infected chimpanzees. However, inâ
vitro potency losses against clinically relevant GT1a variants prompted a further effort to develop compounds with sustained potency across a broader array of HCV genotypes and mutants. Ultimately, a biology and medicinal chemistry collaboration led to the discovery of the development candidate MK-8876. MK-8876 demonstrated a pan-genotypic potency profile and maintained potency against clinically relevant mutants. It demonstrated moderate bioavailability in rats and dogs, but showed low plasma clearance characteristics consistent with once-daily dosing. Herein we describe the efforts which led to the discovery of MK-8876, which advanced into Phaseâ
1 monotherapy studies for evaluation and characterization as a component of an all-oral direct-acting drug regimen for the treatment of chronic HCV infection.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Antivirales
/
Benzofuranos
/
Hepatitis C
/
Hepacivirus
Límite:
Animals
/
Humans
Idioma:
En
Revista:
ChemMedChem
Asunto de la revista:
FARMACOLOGIA
/
QUIMICA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos