Dihydrobenzisoxazole-4-one compounds are novel selective inhibitors of aldosterone synthase (CYP11B2) with in vivo activity.
Bioorg Med Chem Lett
; 28(5): 979-984, 2018 03 01.
Article
em En
| MEDLINE
| ID: mdl-29254646
ABSTRACT
6,7-Dihydro-5H-2,1-benzisoxazol-4-one analogs are potent inhibitors of aldosterone synthase (CYP11B2) with selectivity over the highly homologous enzyme cortisol synthase (CYP11B1). These compounds are unique among inhibitors of CYP11B2 in their lack of a strong-heme binding group such as a pyridine or imidazole. Poor metabolic stability in hepatocyte incubations was found to proceed via a reduction of the isoxazole ring. While the enzyme responsible for the reductive metabolism remains unknown, the rate of metabolism could be attenuated by the addition of polar functionality. The in vitro CYP11B2 potency and selectivity were confirmed in vivo in a cynomolgus monkey model by the inhibition of ACTH stimulated aldosterone production without impacting plasma cortisol concentrations.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Citocromo P-450 CYP11B2
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Inibidores Enzimáticos
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Isoxazóis
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos