Selective inhibitors of aldo-keto reductases AKR1C1 and AKR1C3 discovered by virtual screening of a fragment library.

Human aldo-keto reductases 1C1-1C4 (AKR1C1-AKR1C4) function in vivo as 3-keto-, 17-keto-, and 20-ketosteroid reductases and regulate the activity of androgens, estrogens, and progesterone and the occupancy and transactivation of their corresponding receptors. Aberrant expression and action of AKR1C enzymes can lead to different pathophysiological conditions. AKR1C enzymes thus represent important targets for development of new drugs.

Expression of human aldo-keto reductase 1C2 in cell lines of peritoneal endometriosis: potential implications in metabolism of progesterone and dydrogesterone and inhibition by progestins.

The human aldo-keto reductase AKR1C2 converts 5α-dihydrotestosterone to the less active 3α-androstanediol and has a minor 20-ketosteroid reductase activity that metabolises progesterone to 20α-hydroxyprogesterone. AKR1C2 is expressed in different peripheral tissues, but its role in uterine diseases like endometriosis has not been studied in detail. Some progestins used for treatment of endometriosis inhibit AKR1C1 and AKR1C3, with unknown effects on AKR1C2.

Selectivity and potency of the retroprogesterone dydrogesterone in vitro.

Dydrogesterone is widely used for menstrual disorders, endometriosis, threatened and habitual abortion and postmenopausal hormone replacement therapy. Although progestins have a promiscuous nature, dydrogesterone does not have clinically relevant androgenic, estrogenic, glucocorticoid or mineralocorticoid activities. To date, systematic biochemical characterization of this progestin and its active main metabolite, 20α-dihydrodydrogesterone, has not been performed in comparison to progesterone.

Synthesis and biological evaluation of (6- and 7-phenyl) coumarin derivatives as selective nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1.

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is an enzyme that catalyzes NADPH-dependent reduction of the weak estrogen, estrone, into the most potent estrogen, estradiol, which exerts proliferative effects via the estrogen receptors. Overexpression of 17β-HSD1 in estrogen-responsive tissues is related to the development of hormone-dependent diseases, such as breast cancer and endometriosis; thus, 17β-HSD1 represents an attractive target for the development of new therapies. We have discovered that simple coumarines 1 and 2 significantly inhibit 17β-HSD1 in a recombinant enzyme assay, with high selectivity against 17β-HSD2.

New cyclopentane derivatives as inhibitors of steroid metabolizing enzymes AKR1C1 and AKR1C3.

A series of cyclopentane derivatives was synthesized and evaluated for inhibition of the steroid metabolizing enzymes AKR1C1 and AKR1C3. Selective inhibitors that are active in the low micromolar range were identified. These compounds represent promising starting points in the development of new anticancer agents for the treatment of hormone-dependent forms of cancer and other diseases where AKR1C1 and AKR1C3 are involved.

Flavonoids and cinnamic acid derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1.

17beta-Hydroxysteroid dehydrogenase (17beta-HSD) type 1 converts estrone to estradiol, a potent ligand for estrogen receptors. It represents an important target for the development of drugs for treatment of estrogen-dependent diseases. In the present study, we have examined the inhibitory activities of some flavonoids, their biosynthetic precursors (cinnamic acids and coumaric acid), and their derivatives.

Discovery of new inhibitors of aldo-keto reductase 1C1 by structure-based virtual screening.

Aldo-keto reductase 1C1 is a hydroxysteroid dehydrogenase that inactivates progesterone by converting it to 20alpha-hydroxyprogesterone. It also inactivates 3alpha,5alpha-tetrahydroprogesterone, an allosteric modulator of the gamma-aminobutyric acid receptor that has anaesthetic, analgesic, anxiolytic and anti-convulsant effects. Inhibitors of aldo-keto reductase 1C1 are thus very interesting as potential agents for the treatment of endometrial cancer, premenstrual syndrome, catamenial epilepsy, and depressive disorders, and for the maintenance of pregnancy.

Phytoestrogens as inhibitors of the human progesterone metabolizing enzyme AKR1C1.

Phytoestrogens are plant-derived, non-steroidal constituents of our diets. They can act as agonists or antagonists of estrogen receptors, and they can modulate the activities of the key enzymes in estrogen biosynthesis. Much less is known about their actions on the androgen and progesterone metabolizing enzymes.

Cinnamic acids as new inhibitors of 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3).

17Beta-hydroxysteroid dehydrogenase type 5 (AKR1C3) that is involved in the pre-receptor regulation of androgen and estrogen action in the human is an emerging therapeutic target in the treatment of hormone-dependent forms of cancer, such as prostate cancer, breast cancer and endometrial cancer. To discover novel inhibitors, we tested the effect of a series of cinnamic acids on the reductive activity of the human recombinant AKR1C3. The compounds were evaluated in a spectrophotometric assay using 9,10-phenanthrenequinone as a substrate.

Nonsteroidal anti-inflammatory drugs and their analogues as inhibitors of aldo-keto reductase AKR1C3: new lead compounds for the development of anticancer agents.

Nonsteroidal anti-inflammatory drugs (NSAIDs) like indomethacin, flufenamic acid, and related compounds have been recently identified as potent inhibitors of AKR1C3. We report that some other NSAIDs (diclofenac and naproxen) also inhibit AKR1C3, with the IC(50) values in the low micromolar range. In order to obtain more information about the structure-activity relationship and to identify new leads, a series of compounds designed on the basis of NSAIDs were synthesized and screened on AKR1C3.