RESUMO
A new series of thiazolidine derivatives with an adamantyl group was synthesized and evaluated for their ability to inhibit 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1). Our initial compound 5a showed a weak inhibitory activity. Significant improvements in potency were achieved by substituent modification. The potent compound 8g (E) showed good in vitro inhibitory activity toward human 11ß-HSD1, selectivity toward 11ß-HSD2, metabolic stability, pharmacokinetic, and safety profile. Furthermore, this compound significantly inhibited 11ß-HSD1 activity in rat and monkey models, and showed improved glycemic control in KKAy mice.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/química , Inibidores Enzimáticos/síntese química , Tiazolidinas/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Adamantano/síntese química , Adamantano/farmacocinética , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Haplorrinos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Ratos , Relação Estrutura-Atividade , Tiazolidinas/síntese química , Tiazolidinas/farmacocinéticaRESUMO
In the continuation of our 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitor research, cyclic sulfonamide derivatives with an acetamide group at the 2-position were synthesized and evaluated for their abilities to inhibit 11ß-HSD1. Among this series, Compound 34 showed good in vitro activity toward human 11ß-HSD1, selectivity against 11ß-HSD2, microsomal stability, good pharmacokinetic and safety profiles human ether-a-go-go related gene (hERG and cytochrome P450 (CYP)). Also, a docking study explained the activity difference between human and mouse 11ß-HSD1.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Acetamidas/química , Inibidores Enzimáticos/química , Sulfonamidas/química , Tiazinas/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Animais , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Canal de Potássio ERG1 , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , CamundongosRESUMO
A new series of cyclic sulfonamide derivatives was synthesized and evaluated for their ability to inhibit 11beta-HSD1. Cyclic sulfonamides with phenylacetyl substituents at the 2-position showed nanomolar inhibitory activities. Among them, compound 4e exhibited a good in vitro inhibitory activity and selectivity toward human 11beta-HSD2.