Discovery of a Silicon-Containing Pan-Genotype Hepatitis C Virus NS5A Inhibitor.
J Med Chem
; 63(10): 5312-5323, 2020 05 28.
Article
en En
| MEDLINE
| ID: mdl-32293179
ABSTRACT
We describe a study leading to the discovery of compound 11, a pan-genotypic hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor with excellent potency, metabolic stability, and pharmacokinetics (PK). Compound 11 incorporating a 4-silapiperidine group was discovered by further optimizing our previous lead with a triethylsilyl moiety. It displayed great potency against genotype 1 subtype a (GT1a), -1b, -2a, -3a, -4a, -5a, and -6a with an EC50 range of 0.33-17 pM and improved potency against the resistance-associated variant GT1a_M28T. Pharmacokinetics (PK) study indicated that compound 11 has reasonable PK exposures with a high liver distribution in preclinical animal species (mouse, rat, and dog). The results of a 14 day repeat-dose toxicity study identified the safety of compound 11.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Antivirales
/
Silicio
/
Proteínas no Estructurales Virales
/
Farmacorresistencia Viral
/
Descubrimiento de Drogas
/
Genotipo
Tipo de estudio:
Clinical_trials
Límite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
China