Synthesis and 11 beta hydroxysteroid dehydrogenase 1 inhibition of thiazolidine derivatives with an adamantyl group

A new series of thiazolidine derivatives with an adamantyl group was synthesized and evaluated for their ability to inhibit 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-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 11 beta-HSD1, selectivity toward 11 beta-HSD2, metabolic stability, pharmacokinetic, and safety profile. Furthermore, this compound significantly inhibited 11 beta-HSD1 activity in rat and monkey models, and showed improved glycemic control in KKAy mice. (c) 2010 Elsevier Ltd. All rights reserved.