CONICET | Buscador de Institutos y Recursos Humanos

Antiglucocorticoids that act as antagonists at the GR level may be used to block or modulate the undesirable effects of glucocorticoid excess (from endogenous or exogenous origin). RU-486 developed in the early 80s, is an antiglucocorticoid but also a potent antiprogestin and abortifacient, nevertheless it still remains as the only GR antagonist drug in the market. Further on, in view of the variety of physiological processes in which glucocorticoids are involved, selective antiglucocorticoids that can block only some of these processes (eventually with tissue specificity) would be highly desirable. 21-Hydroxy-6,19-epoxyprogesterone was developed as an alternative lead, being an antagonist of the glucocorticoid receptor with no affinity for mineralocorticoid and progesterone receptors. Antagonistic activity was evidenced by partial blocking of dexamethasone induction of TAT and thymocyte apoptosis. Replacement of the oxygen bridge by a sulfur bridge gave a less bent, more flexible molecule. 21-Hydroxy-6,19-epithioprogesterone exhibited improved antiapoptotic activity on thymocytes but was not effective blocking TAT induction. This selectivity was improved further by oxidation to the sulfone. The sulfone but not the reduced compound also reverted the dexamethasone-mediated inhibition of NFkB activity in Hela cells. Blocking of the apoptotic effect of TNFa by dexamethasone in L929 cell line (mouse fibroblasts) was reverted partially, only by the sulfone which exhibited mild agonistic/antagonistic activity in this assay. None of these compounds showed antiprogestin activity. A similar overall molecular shape but more lipophylic and with higher metabolic stability was attained by introduction of a methylene bridge (6,19-methanoprogesterone). More recently we have synthesized a highly bent steroid with a direct bond between C-6 and C-19 (6,19-cycloprogesterone and its 21-hydroxy derivative). This structure showed affinity for GR.