17-estradiol (E2), the most potent estrogen in human beings, known to be involved in the development and progession of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. biological data with features of the pharmacophore model. Probably the most active keto-derivative 6 shows IC50-ideals in the nanomolar range for the transformation of E1 to E2 by 17-HSD1, sensible selectivity against 17-HSD2 but pronounced affinity to the estrogen receptors (ERs). On the other hand, the best amide-derivative 21 shows only medium 17-HSD1 inhibitory activity at the prospective enzyme as well as fair selectivity against 17-HSD2 and ERs. The compounds 6 and 21 can be regarded as 1st benzothiazole-type 17-HSD1 inhibitors for the development of potential therapeutics. Intro Estrogens are important steroidal hormones which exert different physiological functions. The main beneficial effects include their part in encoding the breast and uterus for sexual reproduction , controlling cholesterol production in ways that limit the build-up of plaque in the coronary arteries , and conserving bone strength by helping to maintain the appropriate balance between bone build-up and breakdown C. Among female sex hormones, 17-estradiol (E2) is the most potent estrogen carrying out its action either via transactivation of estrogen receptors (ERs)  or by revitalizing nongenomic effects via the MAPK (mitogen-activated protein kinase) signaling pathway . In addition to 1197958-12-5 manufacture its important beneficial effects, however, E2 can also cause serious problems arising from its ability to promote the cell proliferation in breast and uterus. Although this is one of the normal functions of estrogen in the body, it can also increase the risk of estrogen dependent diseases (EDD), like breast malignancy, endometriosis and 1197958-12-5 manufacture endometrial hyperplasia C. Suppression of estrogenic effects is consequently a major restorative approach. This is proved by routine medical center use of different endocrine therapies, for instance with GnRH analogues, SERMs (selective estrogen receptor modulators), antiestrogens, and aromatase inhibitors C for the prevention as well as the adjuvant treatment of breast cancer. However, all these therapeutics systemically lower estrogen hormone action and may cause significant side effects such as osteoporosis, thrombosis, 1197958-12-5 manufacture stroke and endometrial malignancy C. Thus, a new approach, which aims at influencing mainly the intracellular E2 production in the diseased cells (intracrine approach), would as a result be a very beneficial improvement for the treatment of EDD. Such a restorative strategy has already been shown to be effective in androgen dependent diseases like benign prostate hyperplasia by using 5-reductase inhibitors C. 17-HSD1, which is responsible for the intracellular NAD(P)H-dependent conversion of the poor estrone E1 into the highly potent estrogen E2, was found overexpressed at mRNA level in breast malignancy cells C and endometriosis . Inhibition of this enzyme is definitely therefore regarded as a novel intracrine strategy in EDD treatment with the prospect of avoiding the systemic side effects of the existing endocrine therapies. Although to day no candidate offers entered clinical tests, the ability of 17-HSD1 inhibitors to reduce the E1 induced tumor growth has been shown using different animal models, indicating that the 17-HSD1 enzyme is definitely a suitable target for the treatment of breast malignancy C. The same effect was also shown by Day time et al. , Laplante et al.  and Kruchten et al. DHRS12  using proliferation assays. In order not to counteract the restorative effectiveness of 17-HSD1 inhibitors it is important that the compounds are selective against 17-hydroxysteroid dehydrogenase type 2 (17-HSD2). This enzyme catalyses the reverse reaction (oxidation of E2 to E1), therefore playing a protecting role against enhanced E2 formation in the diseased estrogen dependent tissues. Potent and selective 17-HSD2 inhibitors for the treatment of osteoporosis were recently reported C. Additionally, to avoid intrinsic estrogenic and systemic effects, the inhibitors should not show affinity to the estrogen receptors and . Several classes of 17-HSD1 inhibitors have been described in the last years C, most of them possessing a steroidal structure. During the past decade, our group reported on four different classes of nonsteroidal 17-HSD1 inhibitors C. Compounds 1C4 (Number 1) show IC50 ideals toward 17-HSD1 in the nanomolar range and high selectivity against 17-HSD2 and the ERs in our biological screening system . Open in a separate window Number 1 Nonsteroidal 17-HSD1 inhibitors published by our group. In our search for fresh nonsteroidal 17-HSD1 inhibitors that are structurally different from those previously explained, an screening of an in-house compound library was performed using a pharmacophore model derived from crystallographic data. Upon experimental validation, a virtual hit could be identified as a moderately active inhibitor of 17-HSD1 (Table S1, compound 5); structural optimization led to the finding of benzothiazoles as novel, potent inhibitors of the prospective enzyme with good biological activity screening tool, a new pharmacophore model for 17-HSD1, centered.