Synthesis of sterically encumbered 11¦Â-aminoprogesterone derivatives and evaluation as 11¦Â-hydroxysteroid dehydrogenase inhibitors and mineralocorticoid receptor antagonists
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- 作者：Keyur P ; ya ; David Dietrich ; Julia Seibert ; John C. Vederas ; Alex Odermatt
- 关键词：11Beta-hydroxysteroid dehydrogenase ; Mineralocorticoid receptor ; Inhibitor ; Antagonist ; Amino acid&ndash ; steroid conjugates ; Glucocorticoid
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2013
- 出版时间：1 November, 2013
- 年：2013
- 卷：21
- 期：21
- 页码：6274-6281
- 全文大小：718 K
文摘
11¦Â-Hydroxyprogesterone is a well-known nonselective inhibitor of 11¦Â-hydroxysteroid dehydrogenase (11¦ÂHSD) types 1 and 2. It also activates the mineralocorticoid receptor (MR). Modulation of corticosteroid action by inhibition of 11¦ÂHSDs 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 11¦Â-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 11¦Â-aminoprogesterone derivatives selectively inhibit 11¦ÂHSD2. Moreover, two compounds that did not significantly inhibit 11¦ÂHSDs had antagonist properties on MR. The 11¦Â-aminoprogesterone derivatives form a basis for the further development of improved modulators of corticosteroid action.