Antiglucocorticoids

Research conducted by Simons using antiglucocorticoids, including compounds which covalentiy bind to the GR (124), eg, dexamethasone 21-mesylate, has better defined the stmcture and function of the GR. Spiro C-17 oxetanes have shown potent antiglucocorticoid activity in whole cell systems (125,126). 

Although both the lOP- and the liP-group have been found to be important in connection with many GR antagonists, neither is a requirement for antiglucocorticoid activity. Cortexolone (15) acts as a GR antagonist in the tme sense of the term, blocking GR transactivation (127—129) although it does not include an liP-substituent. 

Compounds of this type have been shown to retain antiprogestational effects and to have reduced antiglucocorticoid activity (136). 

SAR analyses revealed that unwanted endocrine side effects such as antiglucocorticoid activities were reduced by modifying position C-17. Among a variety of modifications, the 17Q -pentaliuoroethyl side chain (Fig. 15) led... 

Preclinical studies have shown that drospirenone has no androgenic, estrogenic, glucocortico antiglucocorticoid, or antiandrogenic activity. 

Wolkowitz OM, Reus VI, Chan T, et al Antiglucocorticoids in depression and schizophrenia. Paper presented at the annual meeting of the American Psychiatric Association, New York, 1996a... 

ZK 98734 (lilopristone) is a potent experimental progesterone inhibitor and abortifacient in doses of 25 mg twice daily. Like mifepristone, it also appears to have antiglucocorticoid activity. 

An adolescent girl with Cushingoid features and osteoporosis took mifepristone 400 mg/day for its antiglucocorticoid effect in an attempt to prevent further bone loss (16). Her striae, weight gain, and buffalo hump markedly improved, and further bone loss was halted. However, with each of the two 6-month courses of mifepristone (9 months apart) she developed massive simple endometrial hyperplasia and a markedly enlarged uterus. This reverted to normal after withdrawal of mifepristone. 

Mercier L, Miller PA, Simons SS Jr. Antiglucocorticoid steroids have increased agonist activity in fiiose hepatoma cell fines that are more sensitive to glucocorticoids. J. Steroid Biochem. 1986 25 11-20. 

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