Nonsteroidal Selective Glucocorticoid Modulators:  the Effect of C-5 Alkyl Substitution on the Transcriptional Activation/Repression Profile of 2,5-Dihydro-10-methoxy-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines

The preparation and characterization of a series of selective glucocorticoid receptor modulators are described. The preliminary structure−activity relationship of nonaromatic C-5 substitution on the tetracyclic quinoline core showed a preference for small lipophilic side chains. Proper substitution at this position maintained the transcriptional repression of proinflammatory transcription factors while diminishing the transcriptional activation activity of the ligand/glucocorticoid receptor complex. The optimal compounds described in this study were the allyl analogue <BO>18</BO> and cyclopentyl analogue <BO>32</BO>. These candidates showed slightly less potent, highly efficacious E-selectin repression with significantly reduced levels of glucocorticoid response element activation in reporter gene assays vs prednisolone. Allyl analogue <BO>18</BO> was evaluated in vivo. An oral dose of <BO>18</BO> showed an ED<INF>50</INF> = 1.7 mg/kg as compared to 1.2 mg/kg for prednisolone in the Sephadex-induced pulmonary eosinophilia model and an ED<INF>50</INF> = 15 mg/kg vs 4 mg/kg for prednisolone in the carrageenan-induced paw edema model.