Selective 11beta-HSD inhibitors and methods of use thereof
OwnerDavid J. Morris, Andrew S. Breminventors
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Abstract
Methods for treating glucocorticoid associated states using selective 11β-HSD1-dehydrogenase, 11β-HSD1-reductase and 11β-HSD2 dehydrogenase modulating compounds are described.
Claims64
A method for treating a glucocorticoid associated state in a subject, comprising administering to said subject an effective amount of a 11β-HSD1 reductase inhibitor, such that the glucocorticoid associated state is treated, wherein said 11β-HSD 1 reductase inhibitor is 11-keto-testoterone, 11-keto-androsterone, 11-keto-pregnenolone, 11-keto-dehydro-epiandrostenedione, 3α,5α-reduced-11-ketoprogesterone, 3α,5α-reduced-11-keto-testosterone, 3α,5α-reduced-11-keto-androstenedione, 3α,5α-tetrahydro-11β-dehydro-corticosterone, or a pharmaceutically acceptable prodrug or salt thereof.
A method for treating a glucocorticoid associated state in a subject, comprising administering to said subject an effective amount of a 11β-HSD1 reductase inhibitor, such that the glucocorticoid associated state is treated, wherein said 11β-HSD1 reductase inhibitor is a nucleic acid.
A method for treating a glucocorticoid associated state in a subject, comprising administering to said subject an effective amount of a 11β-HSD1 reductase inhibitor in combination with a 17α-hydroxylase inhibitor, 17-HSD inhibitor, 20α-reductase inhibitor, or a 20β-reductase inhibitor.
A method for increasing the concentration of glucocorticoids in a tissue of a subject, comprising administering to a subject an effective amount of a 11β-HSD1 dehydrogenase inhibitor, such that the concentration of glucocorticoids in said tissue are increased, wherein said 11β-HSD1 dehydrogenase inhibitor is 3α,5α-reduced-11β-OH-progesterone, 3α,5α-reduced-11β-OH-testosterone, 3α,5α-reduced-11β-OH-androstendione, 3α,5α-reduced-11β-OH-pregnenolone, 3α,5α-reduced-11β-OH-dehydro-epiandrostenedione, 3α,5α-reduced-corticosterone, 3α,5α-reduced-aldosterone, 3α,5α-reduced-pregnenolone, 3α,5α-reduced-dehydro-epiandrostenedione, 3α,5β-reduced-progesterone, 3α,5β-testosterone, deoxy-corticosterone, 11β-OH progesterone, 11β-OH testosterone, 11β-OH-pregnenolone, 11β-OH-dehydro-epiandrostenedione, 3α,5α-reduced-progesterone, 3α,5α-reduced testosterone, 3α,5α-reduced-chenodeoxycholic acid, or a pharmaceutically acceptable prodrug or salt thereof.
A method for increasing the concentration of glucocorticoids in a tissue of a subject, comprising administering to a subject an effective amount of a 11β-HSD1 dehydrogenase inhibitor, such that the concentration of glucocorticoids in said tissue are increased, wherein said 11β-HSD1 dehydrogenase inhibitor is a nucleic acid.
A method for increasing the concentration of glucocorticoids in a tissue of a subject, comprising administering to a subject an effective amount of a 11β-HSD1 dehydrogenase inhibitor in combination with a 17α-hydroxylase inhibitor, 17HSD inhibitor, 20α-reductase inhibitor or 20β-reductase inhibitor, such that the concentration of glucocorticoids in said tissue are increased.
A method for increasing the concentration of glucocorticoids in a tissue of a subject, comprising administering to a subject an effective amount of a 11β-HSD2 dehydrogenase inhibitor, such that the concentration of glucocorticoids in said tissue are increased, wherein said 11β-HSD2 dehydrogenase inhibitor is a nucleic acid, 3α,5α-reduced-11β-OH-progesterone, 3α,5α-reduced-11β-OH-testosterone, 3α,5α-reduced-11β-OH-androstenedione, 3α,5α-reduced-11-keto-progesterone, 3α,5α-reduced-11-dehydro-corticosterone, 3α,5α-reduced-corticosterone, 3α,5α-aldosterone, 11β-OH progesterone, 11β-OH-testosterone, 11-keto-progesterone, 5α-dihydro-corticosterone, 5α-dihydro-corticosterone, 3α,5α-reduced deoxy-corticosterone or a pharmaceutically acceptable prodrug or salt thereof.
A method for increasing the concentration of glucocorticoids in a tissue of a subject, comprising administering to a subject an effective amount of a 11β-HSD2 dehydrogenase inhibitor in combination with a 17α-hydroxylase inhibitor, 17-HSD inhibitor, 20α-reductase inhibitor, or a 20β-reductase inhibitor, such that the concentration of glucocorticoids in said tissue are increased.
A method for treating hypertension in a subject, comprising administering to said subject an effective amount of a 11β-HSD1 reductase inhibitor, such that said subject is treated, wherein said 11β-HSD1 reductase inhibitor is 11-keto-progesterone, 11-keto-testosterone, 11-keto-androsterone, 11-keto-pregnenolone, 11-keto-dehydro-epiandrostenedione, 3α,5α-reduced-11-keto-progesterone, 3α,5α-reduced-11-keto-testosterone, 3α,5α-reduced-11-keto-androstenedione, 3α,5α-tetrahydro-11-dehydro-corticosterone, 3α,5α-reduced-11-keto-pregnenolone, 3α,5α-reduced-11-keto-dehydro-epiandrostenedione or a pharmaceutically acceptable prodrug or salt thereof.
A method for treating hypertension in a subject, comprising administering to said subject an effective amount of a 11β-HSD1 reductase inhibitor, such that said subject is treated, wherein said 11β-HSD1 reductase inhibitor is a nucleic acid.
A method for treating hypertension in a subject, comprising administering to said subject an effective amount of a 11β-HSD1 reductase inhibitor in combination with a 17α-hydroxylase inhibitor, a 17-HSD inhibitor, a 20α-reductase inhibitor or a 20β-reductase inhibitor, such that said subject is treated.
A method for increasing insulin sensitivity of a tissue in a subject, comprising administering an effective amount of a 11β-HSD1 reductase inhibitor to said subject, such that the insulin sensitivity of said tissue in said subject is increased, wherein said 11β-HSD1 reductase inhibitor is a nucleic acid, 11-keto-progesterone, 11-keto-testosterone, 11-keto-androsterone, 11-keto-pregnenolone, 11-keto-dehydro-epiandrostenedione, 3α,5α-reduced-11-keto-progesterone, 3α,5α-reduced-11-keto-testosterone, 3α,5α-reduced-11-keto-androstenedione, 3α,5α-tetrahydro-11-dehydro-corticosterone, 3α,5α-reduced-11-keto-pregnenolone, and 3α,5α-reduced-11-keto-dehydro-epiandrostenedione or a pharmaceutically acceptable prodrug or salt thereof.
A pharmaceutical composition comprising an effective amount of 11β-OH-progesterone, 11β-OH-testosterone, 3α,5β-reduced-11β-OH-progesterone, 3α,5α-reduced-11 β-OH-testosterone, chenodeoxycholic acid, 3α,5α-reduced-pregneniolone, 3α,5β-reduced-dehydro-epiandrostenedione, 3α,5α-reduced-11β-OH-progesterone, 3α,5α-reduced-11β-OH-testosterone, 3α,5α-reduced-11β-OH-androstenedione, 11-keto-progesterone, 11-keto-testosterone, 11-keto-androstenedione, 3α,5α-reduced-11-keto-progesterone, 3α,5α-reduced-11-keto-testosterone, 3α,5α-reduced-11-keto-androstenedione, 3α,5α-tetrahydro-11-dehydro-corticosterone, 3α,5α-reduced-corticosterone, 5α-dihydro-corticosterone, 3α,5α-reduced-11β-OH-pregnenolone, 3α,5α-reduced-11β-OH-dehydro-epiandrostenedione, 11β-OH-pregnenolone, 11β-OH-dehydro-epiandrostenedione, 3α,5α-reduced-pregnenolone, 3α,5α-reduced-dehydro-epiandrostenedione, 3α,5α-reduced aldosterone, or a pharmaceutically acceptable salt or prodrug thereof, in combination with a 17α-hydroxylase inhibitor, a 17-HSD inhibitor, a 20α-reductase inhibitor, or a 20β-reductase inhibitor.
A composition comprising a 11β-HSD1 reductase inhibitor, wherein said 11β-HSD1 reductase inhibitor is an siRNA.
A composition comprising an 11β-HSD2 dehydrogenase inhibitor, wherein said 11β-HSD2 dehydrogenase inhibitor is an siRNA.
Dependencies are inferred from the claim text.