Abstrakt

Development of HSD-016 and HSD-621 as potential agents for the treatment of type 2 diabetes

Zhao Kui Wan

 The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. We developed a series of potent and selective 11β-HSD1 inhibitors. These compounds showed excellent potency against both human and mouse 11β-HSD1 enzymes and displayed good pharmacokinetics and ex vivo inhibition of the target in mice.Compounds HSD-016 and HSD-621 were ultimately selected as clinical development candidates. Both compounds have attractive overall pharmaceutical profiles and demonstrated good oral bioavailability in mouse, rat and dog. When orally dosed in C57/BL6 diet-induced-obesity (DIO) mice, HSD-016 and HSD-621 were efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, both compoundswere well tolerated in drug safety assessment studies.