RESUMO
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.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Descoberta de Drogas/métodos , Sulfonamidas/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Linhagem Celular , Humanos , Camundongos , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , Sulfonamidas/metabolismo , Sulfonamidas/farmacologiaRESUMO
A new series of cyclic sulfamide derivatives were synthesized and evaluated for their ability to inhibit 11ß-HSD1. Among this series, 18e showed good in vitro activity toward human 11ß-HSD1, selectivity against 11ß-HSD2, microsomal stability, and pharmacokinetic and safety profiles (hERG, CYP, and acute toxicity). Additionally, 18e exhibited good in vivo efficacy in rat and monkey models.
RESUMO
A series of novel indene N-oxide derivatives were prepared by various synthetic methods and evaluated for their ability to activate PPARgamma. The best PPARgamma agonist in this series was 9h, which showed an EC(50) value of 15 nM.