Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384

Abstract

ABT-384 is a potent, selective inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1). One milligram of ABT-384 daily fully inhibited hepatic HSD-1. Establishing the dose that fully inhibits central nervous system (CNS) HSD-1 would enable definitive clinical studies in potential CNS indications. [9,11,12,12-2H4] cortisol (D4 cortisol), a stable labeled tracer, was used to characterize HSD-1 inhibition by ABT-384. D4 cortisol and its products were measured in the plasma and cerebrospinal fluid (CSF) of healthy male volunteers during D4 cortisol infusions, for up to 40 h after five daily doses of 1–50 mg ABT-384. Similar procedures were conducted in control subjects who received no ABT-384. Peripheral HSD-1 inhibition was calculated from plasma levels of D4 cortisol and its products. CNS HSD-1 inhibition was characterized from plasma and CSF levels of D4 cortisol and its products. ABT-384 regimens ⩾2 mg daily maintained peripheral HSD-1 inhibition ⩾88%. ABT-384 1 mg daily maintained peripheral HSD-1 inhibition ⩾81%. No CNS formation of D3 cortisol (the mass-labeled product of HSD-1) was detected following ABT-384 ⩾2 mg daily, indicating full CNS HSD-1 inhibition by these regimens. Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily. CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites. ABT-384 has a wide potential therapeutic window for potential indications including Alzheimer's disease and major depressive disorder. Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets.

Selection and early clinical evaluation of the brain‐penetrant 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) inhibitor UE2343 (Xanamem™)

“…The CSF data for UE2343 compare favourably with data published for ABT‐384, for which the CSF levels were 0.3 to 1% of total plasma levels (Katz et al, ). In this study, the authors also measured deuterated cortisol adducts in the CSF of two subjects in an effort to determine brain‐specific inhibition of 11β‐HSD1, and inferred complete inhibition of brain enzyme at levels of ABT‐384 in the CSF that were well below its cellular IC 50 and which would not be expected to deliver significant 11β‐HSD1 inhibition.…”

11β-Hydroxysteroid Dehydrogenase Activity in the Brain Does Not Contribute to Systemic Interconversion of Cortisol and Cortisone in Healthy Men

“…One previous study has evaluated in vivo 11βHSD1 activity in the brain, by measuring peripheral venous plasma and cerebrospinal fluid (CSF) steroid concentrations during d4-cortisol infusion ( 19 ). Unfortunately, data were presented for only two subjects without administration of a potent 11βHSD1 inhibitor.…”

“…If 11βHSD activity in the brain had been detectable with the approach used here, this could have provided a useful pharmacodynamic tool to quantify brain enzyme inhibition by selective 11βHSD1 inhibitors in development for treatment of dementia ( 14 , 19 ). As things stand, neither this approach nor the CSF approach attempted by Katz et al ( 19 ) appear well-suited for this purpose in healthy volunteers.…”

Anti‐stress Activity of Ocimum sanctum: Possible Effects on Hypothalamic–Pituitary–Adrenal Axis

“…11β-Hydroxysteroid dehydrogenase type 1 is an enzyme that converts inactive cortisone to active cortisol, and excess cortisol formed during the stress conditions leads to Cushing's syndrome, obesity, insulin resistance, hypertension, dyslipidaemia, major depressive disorder, Alzheimer's disease, osteoporosis, and glaucoma (Katz et al, 2013). Hence, an HSD1 inhibitor by blocking regeneration of the cortisol has therapeutic potential in ameliorating the stress-related diseases.…”