11β-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitors represent a potential therapeutic approach for patients with Cushing’s syndrome, autonomous cortisol secretion (ACS), or iatrogenic glucocorticoid (GC) excess. We assessed whether the HSD-1 inhibitor SPI-62 prevents GC-associated morbidity in a mouse Cushing’s syndrome model.

With more potent drug candidates being developed, the incidence of target-mediated drug disposition (TMDD) in small-molecule compounds has significantly increased in the past decade. Moreover, TMDD appears to apply to some small-molecule compound classes. The main purpose of the current review is to increase the awareness of TMDD in a series of small-molecule inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) using ABT-384, SPI-62, MK0916, BMS-823778, and BI-187004 as case examples.

SPI-62 is a selective and potent small-molecule inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1). SPI-62 has demonstrated substantial and complex nonlinear pharmacokinetics (PK) in humans that is characterized by unusually low plasma exposure at low doses, dose-dependent volume of distribution, nonlinear PK following the first dose, and dose-proportional PK at steady state, as well as unusually high accumulation ratios at low doses.