One of the normal functions of AL-39324 estrogen in the body, it can also increase the risk of estrogen dependent diseases, like breast cancer, endometriosis and endometrial hyperplasia. Suppression of estrogenic buy 198978-94-8 effects is consequently a major therapeutic approach. This is proved by routine clinic use of different endocrine therapies, for instance with GnRH analogues, SERMs, antiestrogens, and aromatase inhibitors 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, stroke and endometrial cancer. Thus, a new approach, which aims at affecting predominantly the intracellular E2 production in the diseased tissues, would consequently be a very beneficial improvement for the treatment of EDD. Such a therapeutic strategy has already been shown to be effective in androgen dependent diseases like benign prostate hyperplasia by using 5a-reductase inhibitors. 17b-HSD1, which is responsible for the intracellular NAD Hdependent conversion of the weak estrone E1 into the highly potent estrogen E2, was found overexpressed at mRNA level in breast cancer cells and endometriosis. Inhibition of this enzyme is 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 date no candidate has entered clinical trials, the ability of 17b-HSD1 inhibitors to reduce the E1 induced tumor growth has been shown using different animal models, indicating that the 17b-HSD1 enzyme is a suitable target for the treatment of breast cancer. The same effect was also demonstrated by Day et al., Laplante et al. and Kruchten et al. using in vitro proliferation assays. In order not to counteract the therapeutic efficacy of 17b-HSD1 inhibitors it is important that the compounds are selective against 17b-hydroxysteroid dehydrogenase type 2. This enzyme catalyses the reverse reaction, thus playing a protective role against enhanced E2 formation in the diseased estrogen dependent tissues. Potent and selective 17b- HSD2 inhibitors for the treatment of osteoporosis were recently reported. Additionally, to avoid intrinsic estrogenic and systemic effects, the inhibitors should not show affinity to the estrogen receptors a and b. Several classes of 17b-HSD1 inhibitors have been described in the last years, most of them having a steroidal structure. During the past decade, our group reported on four different classes of nonsteroidal 17b-HSD1 inhibitors. Compounds 1�C4 exhibit IC50 values toward 17b-HSD1 in the nanomolar range and high selectivity against 17b-HSD2 and the ERs in our biological screening system. In our search for new