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.

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Elmore SW, Coghlan MJ, Anderson DD, Pratt JK, Green BE, Wang AX, Stashko MA, Lin CW, Tyree CM, Miner JN, Jacobson PB, Wilcox DM, Lane BC

J Med Chem. 2001 Dec 6;44(25):4481-91.

PubMed ID

11728194 [ View in PubMed

]

Abstract

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 18 and cyclopentyl analogue 32. 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 18 was evaluated in vivo. An oral dose of 18 showed an ED(50) = 1.7 mg/kg as compared to 1.2 mg/kg for prednisolone in the Sephadex-induced pulmonary eosinophilia model and an ED(50) = 15 mg/kg vs 4 mg/kg for prednisolone in the carrageenan-induced paw edema model.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Prednisolone	Glucocorticoid receptor	Ki (nM)	2.4	N/A	N/A	Details
Prednisolone	Glucocorticoid receptor	EC 50 (nM)	2.6	N/A	N/A	Details
Prednisolone	Glucocorticoid receptor	EC 50 (nM)	3.3	N/A	N/A	Details