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The AKR1C aldo-keto reductases (AKR1C1-AKR1C4) are enzymes that interconvert steroidal hormones between their active and inactive forms. In this manner, they can regulate the occupancy and trans-activation of the androgen, estrogen and progesterone receptors. The AKR1C isoforms also have important roles in the production and inactivation of neurosteroids and prostaglandins, and in the metabolism of xenobiotics. They thus represent important emerging drug targets for the development of agents for the treatment of hormone-dependent forms of cancer, like breast, prostate and endometrial cancers, and other diseases, like premenstrual syndrome, endometriosis, catamenial epilepsy and depressive disorders. We present here the physiological roles of these enzymes, along with their structural properties and an overview of the recent developments regarding their inhibitors. The most important strategies of inhibitor design are described, which include the screening of banks of natural compounds (like cinnamic acids, flavonoids, jasmonates, and related compounds), the screening of and structural modifications to non-steroidal anti-inflammatory drugs, the substrate-inspired design of steroidal and nonsteroidal inhibitors, and computer-assisted structure-based inhibitor design.

Carcinogenesis of hormone-related cancers involves hormone-stimulated cell proliferation, which increases the number of cell divisions and the opportunity for random genetic errors. In target tissues, steroid hormones are interconverted between their potent, high affinity forms for their respective receptors and their inactive, low affinity forms. One group of enzymes responsible for these interconversions are the hydroxysteroid dehydrogenases, which regulate ligand access to steroid receptors and thus act at a pre-receptor level. As part of this group, the 17beta-hydroxysteroid dehydrogenases catalyze either oxidation of hydroxyl groups or reduction of keto groups at steroid position C17. The thoroughly characterized 17beta-hydroxysteroid dehydrogenase type 1 activates the less active estrone to estradiol, a potent ligand for estrogen receptors. This isoform is expressed in gonads, where it affects circulating levels of estradiol, and in peripheral tissue, where it regulates ligand occupancy of estrogen receptors. Inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 are thus highly interesting potential therapeutic agents for the control of estrogen-dependent diseases such as endometriosis, as well as breast and ovarian cancers. Here, we present the review on the recent development of inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 published and patented since the previous review of 17beta-hydroxysteroid dehydrogenase inhibitors of Poirier (Curr. Med. Chem., 2003, 10, 453). These inhibitors are divided into two separate groups according to their chemical structures: steroidal and non-steroidal 17beta-hydroxysteroid dehydrogenase type 1 inhibitors. Their estrogenic/ proliferative activities and selectivities over other 17beta-hydroxysteroid dehydrogenases that are involved in local regulation of estrogen action (types 2, 7 and 12) are also presented.

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. We postulated that the introduction of various p-substituted phenyl moieties to position 6 or 7 of the coumarin core using the Suzuki-Miyaura cross-coupling reaction would provide mimetics of steroidal structures with improved inhibition of 17β-HSD1. The best inhibitor in the series proved to be 6a, with an IC(50) of 270 nM, and with exceptional selectivity for 17β-HSD1 over 17β-HSD2 and against the α and β estrogen receptors.

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