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Bioorg Med Chem. 2013 Nov 1;21(21):6274-81. doi: 10.1016/j.bmc.2013.08.068. Epub 2013 Sep 7.

Synthesis of sterically encumbered 11β-aminoprogesterone derivatives and evaluation as 11β-hydroxysteroid dehydrogenase inhibitors and mineralocorticoid receptor antagonists.

Author information

1
Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, Alberta T6G 2G2, Canada.

Abstract

11β-Hydroxyprogesterone is a well-known nonselective inhibitor of 11β-hydroxysteroid dehydrogenase (11βHSD) types 1 and 2. It also activates the mineralocorticoid receptor (MR). Modulation of corticosteroid action by inhibition of 11βHSDs or blocking MR is currently under consideration for treatment of electrolyte disturbances, metabolic diseases and chronic inflammatory disorders. We established conditions to synthesize sterically demanding 11β-aminoprogesterone, which following subsequent nucleophilic or reductive amination, allowed extension of the amino group to prepare amino acid derivatives. Biological testing revealed that some of the 11β-aminoprogesterone derivatives selectively inhibit 11βHSD2. Moreover, two compounds that did not significantly inhibit 11βHSDs had antagonist properties on MR. The 11β-aminoprogesterone derivatives form a basis for the further development of improved modulators of corticosteroid action.

KEYWORDS:

11Beta-hydroxysteroid dehydrogenase; Amino acid–steroid conjugates; Antagonist; Glucocorticoid; Inhibitor; Mineralocorticoid receptor

PMID:
24074876
DOI:
10.1016/j.bmc.2013.08.068
[Indexed for MEDLINE]

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