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 11β-hydroxysteroid-dehydrogenase isoform 2 activity by 5α-reduced (but not 5β) derivatives of adrenocorticosteroids. Steroids 62, 230-237], only derivatives of steroid hormones possessing the 5α-Ring A-reduced configuration selectively inhibited 11β-HSD2-dehydrogenase, whereas their 5β-derivatives were inactive. This present study focuses on an expanded group of endogenous 11-oxygenated, 5α and 5β-Ring A-reduced metabolites of adrenocorticosteroids, and progestogen and androgen steroid hormones. These substances were tested for their inhibitory properties against 11β-HSD2, 11β-HSD1-dehydrogenase and 11β-HSD1 reductase. The present studies showed that the following compounds stand out as potent inhibitors. These are 5α-DH-corticosterone, 3α,5α-TH-corticosterone, 11β-OH-progesterone, 11β-OH-allopregnanolone, 11β-OH- testosterone, and 11β-OH-androstanediol, inhibitors of 11β-HSD1- dehydrogenase; 3α,5α-TH-11-dehydro-corticosterone, 11-keto-progesterone, 11-keto-allopregnanolone, and 11-keto-3β,5α-TH- testosterone, inhibitors of 11β-HSD1 reductase; 3α,5α-TH- aldosterone, 5α-DH-corticosterone, 3α,5α-TH-corticosterone,11- dehydro-corticosterone, 3α,5α-TH-11-dehydro-corticosterone, 11β-OH-progesterone, 11-keto-progesterone, 11β-OH-allopregnanolone, 11-keto-allopregnanolone, 11β-OH-testosterone, and 11-keto-testosterone, inhibitors of 11β-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 11β-HSD isoenzymes.
Latif, Syed A., Hector A. Pardo, Matthew P. Hardy, and David J. Morris. 2005. "Endogenous selective inhibitors of 11β-hydroxysteroid dehydrogenase isoforms 1 and 2 of adrenal origin," Molecular and Cellular Endocrinology 243(1–2): 43–50.