Non-steroidal glucocorticoid receptor antagonists: The race to replace RU-486 for anti-glucocorticoid therapy

Expert Opinion on Therapeutic Patents

Volumn 17, Issue 1, 2007, Pages 59-81

  Mohler, Michael L ^a   He, Yali ^a   Wu, Zhongzhi ^a   Hong, Seoung Soo ^a   Miller, Duane D ^a  

^a GTx Inc   (United States)

Author keywords

Cushing's syndrome; Depression; Diabetes; Dissociated glucocorticoid antagonist; Glucocorticoid receptor; Heart failure; Inflammation anti inflammatory; Non steroidal glucocorticoid antagonist; Passive antagonism; Psychoses; Selective glucocorticoid receptor modulators; Transactivation; Transrepression

Indexed keywords

11BETA (1,3 BENZODIOXOL 5 YL) 17BETA HYDROXY 17ALPHA (1 PROPYNYL)ESTRA 4,9 DIEN 3 ONE; ALDOSTERONE; AMINOGLUTETHIMIDE; BROMOCRIPTINE; CYCLOOCTANE DERIVATIVE; CYPROHEPTADINE; CYPROTERONE ACETATE; DIPHENYL ETHER DERIVATIVE; GLUCOCORTICOID; GLUCOCORTICOID RECEPTOR; GLUCOCORTICOID RECEPTOR ANTAGONIST; GLUCOSE; HYDROCORTISONE; KETOCONAZOLE; METYRAPONE; MIFEPRISTONE; MITOTANE; OCTREOTIDE; ONAPRISTONE; ORG 34116; ORG 34850; PHENANTHRENE DERIVATIVE; PROGESTERONE; RU 43044; STEROID HORMONE RECEPTOR BLOCKING AGENT; SULFONAMIDE; TESTOSTERONE; TRIPHENYLMETHANE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALPROIC ACID; ZK 299;

ADIPOSE TISSUE; CLINICAL TRIAL; CUSHING SYNDROME; DIABETES MELLITUS; DRUG STRUCTURE; GLUCOSE BLOOD LEVEL; HUMAN; HYPERCORTISOLISM; HYPERGLYCEMIA; HYPERTENSION; IMMUNE DEFICIENCY; MENTAL STRESS; MUSCLE ATROPHY; OSTEOPOROSIS; PATENT; PHYSIOLOGICAL STRESS; PSYCHOSIS; PUBLICATION; REVIEW;

EID: 33846132292     PISSN: 13543776     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543776.17.1.59     Document Type: Review

References (50)

1. HEIKINHEIMO O, RANTA S, GRUNBERG S, LAHTEENMAKI P, SPITZ IM: Alterations in the pituitary-thyroid and pituitary-adrenal axes - consequences of long-term mifepristone treatment. Metabolism (1997) 46(3):292-296.
2. GEBHARD R, VAN DER VOORT H, SCHUTS W, SCHOONEN W. 11,21 -Bisphenyl- 19-norpregnane derivatives are selective anti-glucocorticoids. Bioorg. Med. Chem. Lett. (1997) 7(17):2229-2234.
3. THOMSON F, CRAIGHEAD MW. WATSON L, TURNBULL Z, MCINTOSH L, SPEAKE M: European Neuropsychopharmacology (2003) 13:S229
4. CHU JW, MATTHIAS DF, BELANOFF J, SCHATZBERG A, HOFFMAN AR, FELDMAN D: Successful long-term treatment of refractory Cushing's disease with high-dose mifepristone (RU 486). J. Clin. Endocrinol. Metab. (2001) 86(8):3568-3573.
5. SONG IH, GOLD R, STRAUB RH, BURMESTER GR, BUTTGEREIT F. New glucocorticoids on the horizon: repress, don't activate! J. Rheumatol. (2005) 32(7):1199-1207.
6. BELVISI MG, WICK SL, BATTRAM CH: Therapeutic benefit of a dissociated glucocorticoid and the relevance of in vitro separation of transrepression from transactivation activity. J. Immunol. (2001) 166:1975-1982.
7. VAYSSIERE BM, DUPONT S, CHOQUART A. Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit anti-inflammatory activity in vivo. Mol. Endocrinol. (1997) 11:1245-1255.
8. GUMS JG, SMITH JD: Chapter 72: adrenal gland disorders. In: Pharmacotherapy: A Pathophysiologic Approach, Fourth Edition. Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM (Eds). Appleton & Lange, Stamford, CT (1999) 1267-1273.
9. CUSHING HW. The basophilic adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull. Johns Hopkins Hosp. (1932) 50:138-195.
10. MEDVEI VC: The history of Cushing's disease: a controversial tale. J. Royal Soc. Med. (1991) 84:363-366.
11. BISHOP PMF, CLOSE HG: A case of basophil adenoma of the anterior lobe of the pituitary: "Cushing's syndrome". Guy's Hosp. Rep. (1932) 82:143-153.
12. JORES A: Ueber Hormonuntersuchungen bei Morbus Cushing. Klin. Wochenschr. (1945) 14:1348-1352.
13. ALBRIGHT F, PARSON W. BLOOMBERG E: Cushing's syndrome interpreted as hyperadrenocorticism leading to hypergluconeogenesis: results of treatment with testosterone propionate. J. Clin. Endocrinol. (1941) 1:375-381.
14. BEAUREGARD C, DICKSTEIN G, LACROIX A. Classic and recent etiologies of Cushing's syndrome: diagnosis and therapy. Treat. Endocrinol. (2002) 1(2):79-94.
15. WISNIEWSKI AB, BROWN TT, JOHN M et al: Cortisol levels and depression in men and women using heroin and cocaine. Psychoneuroendocrinology (2006) 31(2):250-255.
16. KLING MA, DEMITRACK MA, WHITFIELD HJ: Effects of the glucocorticoid antagonist RU 486 on pituitary-adrenal function in patients with anorexia nervosa and healthy volunteers: enhancement of plasma ACTH and cortisol secretion in underweight patients. Neuroendocrinology (1993) 57(6):1082-1091.
17. O'BRIEN RM, NOISIN EL, SUWANICHKUL A et al.: Hepatic nuclear factor 3- and hormone-regulated expression of the phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein 1 genes. Mol. Cell. Biol. (1995) 15(3):1747-1758.
18. JANTZEN HM, STRÄHLE U, GLOSS B et al: Cooperativity of glucocorticoid response elements located far upstream of the tyrosine aminotransferase gene. Cell (1987) 49(1):29-38.
19. GRENIER J, TOMKIEWICZ C, TROUSSON A et al.: Identification by microarray analysis of aspartate aminotransferase and glutamine synthetase as glucocorticoid target genes in a mouse Schwann cell line. J. Steroid Biochem. Mol. Biol. (2005) 97(4):342-352.
20. GETTYS TW, WATSON PM, TAYLOR IL, COLLINS S: RU-486 (Mifepristone) ameliorates diabetes but does not correct deficient β-adrenergic signaling in adipocytes from mature C57BL/6]-oblob mice. Int. J. Obes. Relat. Metab. Disord. (1997) 21(10):865-873.
21. TWARDOWSKA K, RYBAKOWSKI J: Limbic-hypothalamic-pituitary-adrenal axis in depression: literature review. Psychiatr. Pol. (1996) 30(5):741-755.
22. DEBATTISTA C, BELANOFF J: The use of mifepristone in the treatment of neuropsychiatric disorders. Trends Endocrinol. Metab. (2006) 17(3):117-121.
23. WISNIEWSKI AB, BROWN TT, JOHN M et al.: Cortisol levels and depression in men and women using heroin and cocaine. Psychoneuroendocrinology (2006) 31(2):250-255.
24. KLING MA, DEMITRACK MA, WHITFIELD HJ: Effects of the glucocorticoid antagonist RU 486 on pituitary-adrenal function in patients with anorexia nervosa and healthy volunteers: enhancement of plasma ACTH and cortisol secretion in underweight patients. Neuroendocrinology (1993) 57(6):1082-1091.
25. POMARA N, GREENBERG WM, BRANFORD MD, DORAISWAMY PM: Therapeutic implications of HPA axis abnormalities in Alzheimer's disease: review and update. Pychopharmacol. Bull. (2003) 37(2):120-134.
26. REGELSON W: RU-486: how abortion politics have impacted on a potentially useful drug of broad medical application. Perspect. Biol. Med. (1992) 35(3):330-338.
27. WOLKOWITZ OM, REUS VI: Treatment of depression with antiglucocorticoid drugs. Psychosom. Med. (1999) 61(5):698-711.
28. BUETTI E, KÜHNEL B: Distinct sequence elements involved in the glucocorticoid regulation of the mouse mammary tumor virus promoter identified by linker scanning mutagenesis. J. Mol. Biol. (1989) 190:379-389.]
29. MORGAN BP, SWICK AG, HARGROVE AM et al.: Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists. J. Med. Chem. (2002) 45:2417-2424.
30. CHU J, MATTHIAS DF, BELANOFF J, SCHATZBERG A, HOFFMAN AR, FELDMAN D: Successful long-term treatment of refractory Cushing's disease with high-dose mifepristone (RU-486). J. Clin. Endocrinol. Metab. (2001) 86(8):3568-3573.
31. LIU K: Proceedings of the 222nd American Chemical Society National Meeting. Chicago, USA (2001) MEDI-169.
32. MINER JN, TYREE C, HU J et al.: A nonsteroidal glucocorticoid receptor antagonist. Mol. Endocrin. (2003) 17:117-127.
33. COGHLAN MJ, ELMORE SW, KYM PR, KORT ME: Chapter 17. Selective glucocorticoid receptor modulators. Annu. Rep. Med. Chem. (2002) 37:167-178.
34. LINK JT, SORENSEN BK, PATEL J et al.: Discovery of novel nonsteroidal glucocorticoid receptor modulators. Bioorg. Med. Chem. Lett. (2004) 14:2209-2212.
35. LINK JT, SORENSEN B, PATEL J et al.: Antidiabetic activity of passive nonsteroidal glucocorticoid receptor modulators. J. Med. Chem. (2005) 48(16):5295-5304.
36. NEEL DA, BROWN ML, LANDER PA et al.: 3,3-Bisaryloxindoles as mineralocorticoid receptor antagonists. Bioorg. Med. Chem. Lett. (2005) 15(10):2553-2557.
37. 3 group on binding and agonist activity of a glucocorticoid receptor ligand. Bioorg. Med. Chem. Lett. (2005) 15:4761-4769.
38. MACDIARMID F, WANG D, DUNCAN LJ, PUROHIT A, GHILCHICK MW, REED MJ: Stimulation of aromatase activity in breast fibroblasts by tumor necrosis factor α. Mol. Cell. Endocrinol. (1994) 106(1-2):17-21.
39. AKRITOPOULOU-ZANZE I, PATEL JR, HARTANDI K et al.: Synthesis and biological evaluation of novel, selective, nonsteroidal glucocorticoid receptor antagonists. Bioorg. Med Chem. Lett. (2004) 14:2079-2082.
40. DOGGRELL SA: Is AL-438 likely to have fewer side effects than the glucocorticoids? Expert Opin. Invest. Drugs (2003) 12(7):1227-1230.
41. TAKAHASHI H, BEKKALI Y, CAPOLINO AJ et al.: Discovery and SAR study of novel dihydroquinoline containing glucocorticoid receptor ligands. Bioorg. Med. Chem. Lett. (2006) 16(6):1549-1552.
42. HIRSCHMANN R, STEINBERG NG, BUCHSCHACHER P et al.: Synthesis and structure of steroidal 4-pregneno [3,2-c]pyrazoles. A novel class of potent anti-inflammatory steroids. J. Amer. Chem. Soc. (1963) 85(1):120-122
43. DAVIES S, DAI D, PICKETT G, LESLIE KK: Gene regulation profiles by progesterone and doxamethasone in human endometrial cancer Ishikawa H cells. Gynecol. Oncol. (2006) 101(1):62-70.
44. HONER C, NAM K, FINK C et al.: Glucocorticoid receptor antagonism by cyproterone acetate and RU-486. Mol. Pharmacol. (2003) 63(5):1012-1020.
45. WEBB P, NGUYEN NH, CHIELLINI G et al.; Design of thyroid hormone receptor antagonists from first principles. J. Steroid Biochem. Mol. Biol. (2002) 83(1-5):59-73.
46. BRZOZOWSKI AM, PIKE AC, DAUTER Z et al.: Molecular basis of agonism and antagonism in the oestrogen receptor. Nature (1997) 389:753-758.
47. KAUPPI B, JAKOB C, FARNEGARDH M et al.: The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism. J. Biol. Chem. (2003) 278(25):22748-22754.
48. SHIAU AK, BARSTAD D, RADEK JT et al.: Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism. Nat. Struct. Biol. (2002) 9(5):359-364.
49. VON GELDERN TW, TU N, KYM PR et al.: Liver-selectivc glucocorticoid antagonists: a novel treatment for Type 2 diabetes. J. Med. Chem. (2004) 47:4213-4230.
50. JACOBSON PB, VON GELDERN TW, OHMAN L et al.: Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of Type 2 diabetes. J. Pharmacol. Exp. Ther. (2005) 314:191-200.