ABSTRACT
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.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Acetamides/chemistry , Enzyme Inhibitors/chemistry , Sulfonamides/chemistry , Thiazines/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Animals , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , ERG1 Potassium Channel , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Humans , MiceABSTRACT
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.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/analogs & derivatives , Adamantane/chemistry , Enzyme Inhibitors/chemical synthesis , Thiazolidines/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Adamantane/chemical synthesis , Adamantane/pharmacokinetics , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Haplorhini , Humans , Mice , Microsomes, Liver/metabolism , Rats , Structure-Activity Relationship , Thiazolidines/chemical synthesis , Thiazolidines/pharmacokineticsABSTRACT
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.
