Nonsteroidal selective glucocorticoid modulators: the effect of C-10 substitution on receptor selectivity and functional potency of 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines.

摘要: The preparation and characterization of a series C-10 substituted 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines as novel class selective ligands for the glucocorticoid receptor is described. Substitution at position tetracyclic core with linear, two-atom appendages (OCH3, OCF2H, NHMe, SMe, CHCH2, C⋮CH, CH2OH) provided molecules high affinity (Ki = 2−8 nM) human (hGR) limited cross-reactivity other steroid receptors (PR, MR, AR, ER). Optimal analogues showed slightly less potent but highly efficacious E-selectin repression reduced levels GRE activation efficacy in reporter gene assays relative to prednisolone. Preliminary SAR containing substitution C-9 positions identified 9-OH, 10-OMe analogue 50 10-Cl 58 compounds that demonstrated potent, GR-mediated inhibition conconavalin A stimulated T-cell proliferation assay both rodent w...