Glucocorticoid receptor antagonists: new tools to investigate disorders characterized by cortisol hypersecretion.
Increased cortisol levels have been observed in patients suffering from a number of metabolic and psychiatric disorders. In some of these disorders a causal relationship has been suggested between the increased cortisol secretion and the observed clinical phenomena. Glucocorticoid receptor antagonists which block cortisol effects might have a benefit in both the diagnosis and treatment of these disorders. Selective glucocorticoid receptor antagonists with in vivo potency have not been described thus far, partly due to the similarity between the glucocorticoid and progesterone receptors. In the present studies, we report on three different chemical classes derived from the glucocorticoid/progestagen antagonist RU486. Selected compounds from the classes 11-monoaryl steroids, 11,21-bisaryl steroids and 11-aryl, 16-hydroxy steroids proved to be selective glucocorticoid receptor binders with in vivo antagonistic activity. Most compounds were able to pass the blood-brain barrier. These compounds offer the opportunity to investigate and possibly treat patients with a disturbed hypothalamus-pituitary-adrenal axis without side effects caused by an antiprogestagenic action.
Peeters
B W M M
BW
N.V. Organon, Oss, The Netherlands.
Tonnaer
J A D M
JA
Groen
M B
MB
Broekkamp
C L E
CL
van der Voort
H A A
HA
Schoonen
W G F J
WG
Smets
R J M
RJ
Vanderheyden
P M L
PM
Gebhard
R
R
Ruigt
G S F
GS
D000818:Animals; D001812:Blood-Brain Barrier; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism / Q000502:physiology*; D015735:Mifepristone / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D018161:Receptors, Mineralocorticoid / Q000187:drug effects; D011980:Receptors, Progesterone / Q000187:drug effects
D006727:Hormone Antagonists; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011980:Receptors, Progesterone; D015735:Mifepristone; D006854:Hydrocortisone