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

D. A. Katz, W. Liu, C. Locke, P. Jacobson, D. M. Barnes, R. Basu, G. An, M. J. Rieser, D. Daszkowski, F. Groves, G. Heneghan, A. Shah, H. Gevorkyan, S. S. Jhee, L. Ereshefsky, G. J. Marek

Research output: Contribution to journalArticle

9 Citations (Scopus)

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-(2)H4] 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.

Original languageEnglish (US)
JournalTranslational Psychiatry
Volume3
StatePublished - 2013
Externally publishedYes

Fingerprint

11-beta-Hydroxysteroid Dehydrogenases
Hydroxysteroid Dehydrogenases
Peripheral Nervous System
Central Nervous System
Hydrocortisone
Cerebrospinal Fluid
N-(5-(aminocarbonyl)tricyclo(3.3.1.13,7)dec-2-yl)-alpha,alpha-dimethyl-4-(5-(trifluoromethyl)-2-pyridinyl)-1-piperazineacetamide
11-beta-Hydroxysteroid Dehydrogenase Type 1
Inhibition (Psychology)
Major Depressive Disorder
Healthy Volunteers
Alzheimer Disease

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry
  • Cellular and Molecular Neuroscience

Cite this

Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384. / Katz, D. A.; Liu, W.; Locke, C.; Jacobson, P.; Barnes, D. M.; Basu, R.; An, G.; Rieser, M. J.; Daszkowski, D.; Groves, F.; Heneghan, G.; Shah, A.; Gevorkyan, H.; Jhee, S. S.; Ereshefsky, L.; Marek, G. J.

In: Translational Psychiatry, Vol. 3, 2013.

Research output: Contribution to journalArticle

Katz, DA, Liu, W, Locke, C, Jacobson, P, Barnes, DM, Basu, R, An, G, Rieser, MJ, Daszkowski, D, Groves, F, Heneghan, G, Shah, A, Gevorkyan, H, Jhee, SS, Ereshefsky, L & Marek, GJ 2013, 'Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384.', Translational Psychiatry, vol. 3.
Katz, D. A. ; Liu, W. ; Locke, C. ; Jacobson, P. ; Barnes, D. M. ; Basu, R. ; An, G. ; Rieser, M. J. ; Daszkowski, D. ; Groves, F. ; Heneghan, G. ; Shah, A. ; Gevorkyan, H. ; Jhee, S. S. ; Ereshefsky, L. ; Marek, G. J. / Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384. In: Translational Psychiatry. 2013 ; Vol. 3.
@article{77a0d225083c4fc490ffcb7c9ebdc729,
title = "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-(2)H4] 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.",
author = "Katz, {D. A.} and W. Liu and C. Locke and P. Jacobson and Barnes, {D. M.} and R. Basu and G. An and Rieser, {M. J.} and D. Daszkowski and F. Groves and G. Heneghan and A. Shah and H. Gevorkyan and Jhee, {S. S.} and L. Ereshefsky and Marek, {G. J.}",
year = "2013",
language = "English (US)",
volume = "3",
journal = "Translational Psychiatry",
issn = "2158-3188",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Peripheral and central nervous system inhibition of 11β-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384.

AU - Katz, D. A.

AU - Liu, W.

AU - Locke, C.

AU - Jacobson, P.

AU - Barnes, D. M.

AU - Basu, R.

AU - An, G.

AU - Rieser, M. J.

AU - Daszkowski, D.

AU - Groves, F.

AU - Heneghan, G.

AU - Shah, A.

AU - Gevorkyan, H.

AU - Jhee, S. S.

AU - Ereshefsky, L.

AU - Marek, G. J.

PY - 2013

Y1 - 2013

N2 - 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-(2)H4] 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.

AB - 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-(2)H4] 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.

UR - http://www.scopus.com/inward/record.url?scp=84901860544&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901860544&partnerID=8YFLogxK

M3 - Article

C2 - 23982627

AN - SCOPUS:84901860544

VL - 3

JO - Translational Psychiatry

JF - Translational Psychiatry

SN - 2158-3188

ER -