Discovery of a novel 2-spiroproline steroid mimetic scaffold for the potent inhibition of 1113-HSD1

1113-hydroxysteroid dehydrogenase 1 (1113-HSD1) has been identified as the primary enzyme responsible for the activation of hepatic cortisone to cortisol in specific peripheral tissues, resulting in the concomitant antagonism of insulin action within these tissues. Dysregulation of 1113-HSD1, particularly in adipose tissues, has been associated with a variety of ailments including metabolic syndrome and type 2 diabetes mellitus. Therefore, inhibition of 1113-HSD1 with a small nonsteroidal molecule is therapeutically desirable. Implementation of a scaffold-hopping approach revealed a 3-point pharmacophore for 1113-HSD1 that was utilized to design a 2-spi-roproline derivative as a steroid mimetic scaffold. Reiterative optimization provided valuable insight into the bioactive conformation of our novel scaffold and led to the discovery of several leads, such as compounds 39 and 51. Importantly, deleterious hERG inhibition and pregnane X receptor induction were mitigated by the intro-duction of a 4-hydroxyl group to the proline ring system.

Automated summary

1113-HSD1 is the primary enzyme responsible for activating cortisone to cortisol. Dysregulation of 1113-HSD1 has been associated with metabolic syndrome and type 2 diabetes mellitus. Designing a steroid mimetic scaffold can inhibit the activity of 1113-HSD1.