| Substituted phenyl aziridine precursor analogs as modulators of steroid receptor activities -> Monitor Keywords |
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Substituted phenyl aziridine precursor analogs as modulators of steroid receptor activitiesSubstituted phenyl aziridine precursor analogs as modulators of steroid receptor activities description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20090156672, Substituted phenyl aziridine precursor analogs as modulators of steroid receptor activities. Brief Patent Description - Full Patent Description - Patent Application Claims
The present application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application No. 61/014,225, filed on Dec. 17, 2007, the content of which is incorporated herein by reference. Steroid hormone receptors such as androgen receptor (AR) or glucocorticoid receptor (GR) are observed transcription factors that regulate gene expression. In non-activated cells each receptor resides in the cytoplasm in a complex with chaperone proteins. Upon activation by corresponding steroid hormones (e.g., where GR is activated by glucocorticoids and AR is activated by androgens) steroid hormone receptors dissociate from the chaperones, form homo-dimers and enter the nucleus where they interact with the regulatory sequences in gene promoters. Signaling mediated through the steroid hormone receptors plays a pivotal role in the development of diseases and disorders such as prostate cancer (PC). Androgens and androgen receptor (AR) promote the development and progression of PC (Feldman et al., and Heinlein et al.). In contrast, signaling mediated by the glucocorticoid receptor (GR) plays a tumor suppressor role in prostate (Dondi et al., Nishimura et al., Smith et al., Yano et al., and Yemelyanov et al.). As activation of AR and GR have opposite effect on PC cells, the multi-target steroid receptor modulators that positively regulate GR- and negatively regulate AR-mediated signaling may be more effective for PC chemotherapy than single-target compounds. 2-(4-acetoxyphenyl )-2-chloro-N-methyl-ethylammonium chloride, also called Compound A (CpdA), is a synthetic analog of the highly labile aziridine precursor found in the African shrub Salsola tuberculatiformis. Botschantzev (Swart et al. 2003). The aqueous extract of this plant has been used by Bushmen women as a traditional medicine (Swart et al. 2003). It has been shown recently that CpdA directly interacts with steroid receptors AR and GR (De Bosscher et al. 2005, and Tanner et al.). Importantly, CpdA inhibits AR function and strongly enhances the anti-inflammatory function of GR. CpdA does not compete with androgen for AR binding, but similar to well-characterized anti-androgens, represses the activation of AR by inhibition of the androgen-dependent interaction between NH2— and COOH-terminal domains of the AR (Tanner et al.). At the same time, CpdA acts as a non-steroidal GR ligand as it competes with glucocorticoids for GR binding and induces GR translocation into the nucleus (De Bosscher et al. 2005). There are two major mechanisms underlying gene regulation by GR: (i) positive regulation (transactivation) that requires GR binding to glucocorticoid-response elements in gene promoters and (ii) negative regulation (transrepression) that is mediated via negative interaction between GR and other transcription factors, such as NF-κB and AP-1 (De Bosscher et al. 2003, Schacke et al. 2002, and Yemelyanov et al.). It is well understood that many therapeutic anti-inflammatory effects of glucocorticoids are mediated via gene transrepression. In contrast, many undesirable side effects are mediated via DNA-dependent transactivation. It was shown that CpdA possesses the properties of the “dissociated” GR ligand that does not affect GR transactivation potential but induces GR-mediated transrepression (De Bosscher et al. 2005, and Tanner et al.). Furthermore, in in vivo experiments, CpdA acts as a strong anti-inflammatory compound with reduced side effects (De Bosscher et al. 2005). The effect of CpdA on cell growth has never been studied. Here, the effect of CpdA on the growth of several PC cell lines and non-transformed prostate cells is studied. CpdA is observed not to significantly affect non-transformed prostate cells, but to have strong growth inhibitory and pro-apoptotic effects in several prostate carcinoma cell lines. CpdA is observed to induce the overall “normalization” of PC cell phenotype. Moreover, CpdA is much more effective in terms of inhibition of growth and survival of PC cells than glucocorticoids. This suggests that CpdA is a unique multi-target steroid receptor modulator that could be used in the future for the treatment of patients with PC and other diseases or disorders that are mediated by steroid hormone receptors. Disclosed are methods, compounds, and pharmaceutical compositions for treating diseases, disorders or conditions in a patient in need thereof The diseases, disorders, or conditions typically are associated with steroid receptor activities and are responsive to modulation of steroid receptor activities. The methods typically include administering to the patient a therapeutically effective amount of a compound having formula (I), its aziridine derivatives, analogs, or pharmaceutically acceptable salts thereof:
where R is a hydrogen or —C(O)-Z, where Z is a branched or straight chain C1-C6 alkyl group;
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