Synthesis and Characterization of Non-Steroidal Ligands for the Glucocorticoid Receptor: Selective Quinoline Derivatives with Prednisolone-Equivalent Functional Activity

Abstract

A novel class of functional ligands for the human glucocorticoid receptor is described. Substituents in the C-10 position of the tetracyclic core are essential for glucocorticoid receptor (GR) selectivity versus other steroid receptors. The C-5 position is derivatized with meta-substituted aromatic groups, resulting in analogues with a high affinity for GR (K_i = 2.4−9.3 nM) and functional activity comparable to prednisolone in reporter gene assays of glucocorticoid-mediated gene transcription. The biological activity of these novel quinolines was also prednisolone-equivalent in whole cell assays of glucocorticoid function, and compound 13 was similar to prednisolone (po ED₅₀ = 2.8 mpk for 13 vs ED₅₀ = 1.2 mpk for prednisolone) in a rodent model of asthma (sephadex-induced eosinophil influx).