Peptidomimetic inhibitors of herpes simplex virus ribonucleotide reductase with improved in vivo antiviral activity.
J Med Chem
; 39(21): 4173-80, 1996 Oct 11.
Article
en En
| MEDLINE
| ID: mdl-8863795
We have been investigating the potential of a new class of antiviral compounds. These peptidomimetic derivatives prevent association of the two subunits of herpes simplex virus (HSV) ribonucleotide reductase (RR), an enzyme necessary for efficient replication of viral DNA. The compounds disclosed in this paper build on our previously published work. Structure-activity studies reveal beneficial modifications that result in improved antiviral potency in cell culture in a murine ocular model of HSV-induced keratitis. These modifications include a stereochemically defined (2,6-dimethylcyclohexyl)amino N-terminus, two ketomethylene amide bond isosteres, and a (1-ethylneopentyl)amino C-terminus. These three modifications led to the preparation of BILD 1351, our most potent antiherpetic agent containing a ureido N-terminus. Incorporation of the C-terminal modification into our inhibitor series based on a (phenylpropionyl)valine N-terminus provided BILD 1357, a significantly more potent antiviral compound than our previously published best compound, BILD 1263.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Antivirales
/
Oligopéptidos
/
Ribonucleótido Reductasas
/
Urea
/
Simplexvirus
/
Dipéptidos
/
Inhibidores Enzimáticos
Límite:
Animals
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1996
Tipo del documento:
Article
País de afiliación:
Canadá
Pais de publicación:
Estados Unidos