Use of estrone derivatives as steroid sulphatase inhibitors

Details Use of estrone derivatives as steroid sulphatase inhibitors Use of estrone derivatives as steroid sulphatase inhibitors

1997-04-14

2000-01-11

Criares, Theodore J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

514177, 514178, 514182, 514169, 514170, A61K 3166, A61K 3156

Patent

active

060136421

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to a new medical use for certain compounds. In particular it relates to the use of inhibitors which prevent the normal physiological effect of DHEA or related steroids on immune and/or inflammatory responses and most especially to the use of inhibitors of a steroid sulphate sulphatase in revealing an endogenous glucocorticoid effect.


BACKGROUND OF THE INVENTION

Dehydroepiandrosterone (DHEA) is a mild androgenic steroid produced by the adrenal cortex and gonads in men and by the gonads in rodents. In all species it is partly under hypothalamo-pituitary control and formed from common steroid precursors. Although DHEA may act as a precursor for more physiologically active androgenic steroids (e.g. testosterone) it is normally secreted as a hormone in its own right. DHEA is rapidly sulphated to DHEA sulphate (DHEAS) before release into the circulation and it is this latter species which constitutes the main circulating form of the steroid. Outside of the CNS DHEAS is itself inactive. To exert physiological effects it must be desulphated by a steroid sulphate sulphatase at the target site and therefore is able to influence local biological events.
Circulating DHEAS levels decline with age (unlike other steroids) and there is some evidence suggesting that exogenous DHEA administration in mice can reverse some of the physiological events associated with the aged phenotype (Daynes et al (1993) The Journal of Immunology, Vol 150: 12, 5219-5230). For example, administration of DHEAS can reverse the increase in IL-6 production in aged mice (Daynes et al (1993) The Journal of Immunology. Vol 150: 12, 5219-5230). In addition, DHEA may regulate insulin sensitivity of adlpocytes and skeletal muscle (Cleary, (1991) P.S.E.B.M. Vol 196: 8-17) However, its major physiological role may be its ability to influence immune responses.
The immune response to antigen is generally either cell mediated (T-cell mediated killing via processed antigens) or humoral (antibody production via recognition of whole antigen). The pattern of cytokine production by T.sub.H cells involved in the immune response can influence which of these response types predominates: cell mediated immunity (T.sub.H1) is characterised by high IL-2 and IFNg but low IL-4 production, whereas in humoral immunity (T.sub.H2) the pattern is low IL-2 and IFNg but high IL-4, IL-5, IL-10. Since the secretory pattern is modulated at the level of the secondary lymphoid organ then pharmacological manipulation of the specific TH cytokine pattern can influence the type and extent of the immune response generated.
It is well established that administration of exogenous glucocorticoids to ovalbumin-sensitised mice (and other species) induces immunosuppression in which spleen cells show a reduced capacity to secrete IL-2 but are able to enhance IL-4 secretion upon antigen challenge. In contrast, DHEA or DHEAS administration markedly augments IL-2 and IFNg secretion without affecting IL-4 release (Daynes et al (1990) Eur. J. Immunol. 20 793-802). When DHEA and dexamethasone are co-administered, the DHEA effect predominates which is consistent with DHEA acting as an anti-glucocorticoid in this and other systems (Daynes et al (1990) Eur. J. Immunol. 20 793-802), Browne et al (1992) The American Journal of the Medical Sciences 303 No. 6, 366-371 and Blauer et al (1991) Endocrinology 129 No. 6, 3174-3179). These differing responses of glucocorticoids and DHEA are indicative of T.sub.H2 and T.sub.H1 type cytokine patterns respectively, suggesting that they can differentially influence immune responses. Similar effects are seen if spleen cells from sensitized animals are treated with anti-CD3 in the presence of either DHEA, DHEAS or dexamethasone (Daynes et al (1990) J. Exp. Med. 171 979-996).
The immunostimulatory response to biologically inactive DHEAS indicates that there is conversion by steroid sulphate sulphatase within the confines of the secondary lymphoid tissue to the active DHEA. The location of the converting enzyme (steroid s

REFERENCES:
patent: 5281587 (1994-01-01), Reed
Akwa et al. (1992) Biochem. J. 288:959-64.
Birnbock et al. (1990) Biochem. Pharmcol. 39:1709-13.
Blauer et al. (1991) Endocrinology 129:3174-9.
Browne et al. (1992) Am. J. Med. Sci. 303:366-71.
Chang et al. (1993) Biochem. J. 291:429-34.
Daynes et al. (1990) J. Exp. Med. 171:979-96.
Daynes et al. (1990) Eur. J. Immunol. 20:793-802.
Dibbelt et al. (1994) J. Steroid Biochem Mol. Biol. 50:261-6.
Duncan et al. (1993) Cancer Res. 53:298-303.
Hennebold et al. (1994) Endocrinology 135:67-75.
Howarth et al. (1993) Bioorganic Med. Chem. Lett. 3:313-8.
Howarth et al. (1994) J. Med Chem. 37:219-21.
Khalil et al. (1994) J. Steroid Biochem. Mol. Bio. 48:545-52.
Labrie et al. (1992) Cancer Res. 52:610-5.
Li et al. (1993) Steroids 58:106-111.
Meikle et al. (1992) J. Steroid Biochem. Mol. Biol. 42:293-304.
Suzuki et al. (1991) Clinical Immunology Immunopathol. 61:202-11.
Waxman, D.J. (1991) Methods in Enzymol. 206:462-76.
Howarth et al.; Estrone Sulfamates; Potent Inhibitors of Estrone Sulfatase with Therapeutic Potential; J. Med. Chem. vol. 37, pp. 219-221, Jan. 1997.

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