Endogenous selective inhibitors of 11β-hydroxysteroid dehydrogenase isoforms 1 and 2 of adrenal origin

In earlier studies [Latif, S.A., Sheff, M.F., Ribeiro, C.E., Morris, D.J., 1997. Selective inhibition of sheep kidney 11 beta-hydroxysteroiddehydrogenase isoform 2 activity by 5 alpha-reduced (but not 5 beta) derivatives of adrenocorticosteroids. Steroids 62, 230-237], only derivatives of steroid hormones possessing the 5 alpha-Ring A-reduced configuration selectively inhibited 11 beta-HSD2-dehydrogenase, whereas their 5 beta-derivatives were inactive. This present study focuses on an expanded group of endogenous 11-oxygenated, 5 alpha and 5 beta-Ring A-reduced metabolites of adrenocorticosteroids, and progestogen and androgen steroid hormones. These substances were tested for their inhibitory properties against 11 beta-HSD2, 11 beta-HSD1-dehydrogenase and 11 beta-HSD1 reductase. The present studies showed that the following compounds stand out as potent inhibitors. These are 5 alpha-DH-corticosterone, 3 alpha,5 alpha-TH-corticosterone, 11 beta-OH-progesterone, 11 beta-OH-allopregnanolone, 11 beta-OH-testosterone, and 11 beta-OH-androstanediol, inhibitors of 11 beta-HSD1-dehydrogenase; 3 alpha,5 alpha-TH-11-dehydro-corticosterone, 11-keto-progesterone, 11-keto-allopregnanolone, and 11-keto-3 beta,5 alpha-TH-testosterone, inhibitors of 11 beta-HSD1 reductase; 3 alpha,5 alpha-TH-aldosterone, 5 alpha-DH-corticosterone,3 alpha,5 alpha-TH-corticosterone,11-deehydro-corticosterone, 3 alpha,5 alpha-TH-11-dehydro-corticosterone, 11 beta-OH-progesterone, 11-keto-progesterone, 11 beta-OH-allopreananolone, 11-keto-allopreananolone, 11 beta-OH-testosterone, and 11-keto-testosterone, inhibitors of 11 beta-HSD2. All of these substances have the potential to be derived from adrenally synthesized corticosteroids. Substances with similar structures to those described may help in the design of exogenous agents for the management of a variety of disease states involving 11 beta-HSD isoenzymes. (c) 2005 Elsevier Ireland Ltd. All rights reserved.