Synthesis of sterically encumbered 11β-aminoprogesterone derivatives and evaluation as 11β-hydroxysteroid dehydrogenase inhibitors and mineralocorticoid receptor antagonists.
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.
Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, Alberta T6G 2G2, Canada.
Keyur
K
Pandya
David
D
Dietrich
Julia
J
Seibert
John C
JC
Vederas
Alex
A
Odermatt
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000586:Amination; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000451:Mineralocorticoid Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D011374:Progesterone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism; D011485:Protein Binding; D018161:Receptors, Mineralocorticoid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
C588110:11beta-aminoprogesterone; D000596:Amino Acids; D004791:Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D011374:Progesterone; D042842:11-beta-Hydroxysteroid Dehydrogenases
11Beta-hydroxysteroid dehydrogenase; Amino acid–steroid conjugates; Antagonist; Glucocorticoid; Inhibitor; Mineralocorticoid receptor