Synthesis and characterization of non-steroidal ligands for the glucocorticoid receptor: Selective quinoline derivatives with prednisolone-equivalentfunctional activity
Mj. Coghlan et al., Synthesis and characterization of non-steroidal ligands for the glucocorticoid receptor: Selective quinoline derivatives with prednisolone-equivalentfunctional activity, J MED CHEM, 44(18), 2001, pp. 2879-2885
A novel class of functional ligands for the human glucocorticoid receptor i
s 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 n
M) and functional activity comparable to prednisolone in reporter gene assa
ys of glucocorticoid-mediated gene transcription. The biological activity o
f these novel quinolines was also prednisolone-equivalent in whole cell ass
ays 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).