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ID: ALA3871302

Journal: Bioorg Med Chem Lett

Title: Synthesis of novel steroidal agonists, partial agonists, and antagonists for the glucocorticoid receptor.

Authors: Jin Z, Lin H, Srinivasan S, Nwachukwu JC, Bruno N, Griffin PR, Nettles KW, Kamenecka TM.

Abstract: Adverse effects of glucocorticoids could be limited by developing new compounds that selectively modulate anti-inflammatory activity of the glucocorticoid receptor (GR). We have synthesized a novel series of steroidal GR ligands, including potent agonists, partial agonists and antagonists with a wide range of effects on inhibiting secretion of interleukin-6. Some of these new ligands were designed to directly impact conformational stability of helix-12, in the GR ligand-binding domain (LBD). These compounds modulated GR activity and glucocorticoid-induced gene expression in a manner that was inversely correlated to the degree of inflammatory response. In contrast, compounds designed to directly modulate LBD epitopes outside helix-12, led to dissociated levels of GR-mediated gene expression and inflammatory response. Therefore, these new series of compounds and their derivatives will be useful to dissect the ligand-dependent features of GR signaling specificity.

CiteXplore: 27919657

DOI: 10.1016/j.bmcl.2016.11.007