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

S W Elmore; M J Coghlan; D D Anderson; J K Pratt; B E Green; A X Wang; M A Stashko; C W Lin; C M Tyree; J N Miner; P B Jacobson; D M Wilcox; B C Lane

doi:10.1021/jm010367u

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

J Med Chem. 2001 Dec 6;44(25):4481-91. doi: 10.1021/jm010367u.

Authors

S W Elmore¹, M J Coghlan, D D Anderson, J K Pratt, B E Green, A X Wang, M A Stashko, C W Lin, C M Tyree, J N Miner, P B Jacobson, D M Wilcox, B C Lane

Affiliation

¹ Immunologic Disease Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA. steve.elmore@abbott.com

PMID: 11728194
DOI: 10.1021/jm010367u

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.

MeSH terms

Animals
Benzopyrans / chemical synthesis*
Benzopyrans / chemistry
Benzopyrans / pharmacology
Binding, Competitive
Carrageenan
Cell Line
Chlorocebus aethiops
Depression, Chemical
E-Selectin / genetics
E-Selectin / metabolism
Edema / chemically induced
Edema / pathology
Eosinophils / pathology
Genes, Reporter
Humans
Insecta
Luciferases / genetics
Luciferases / metabolism
Male
NF-kappa B / genetics
NF-kappa B / metabolism
Pneumonia / pathology
Quinolines / chemical synthesis*
Quinolines / chemistry
Quinolines / pharmacology
Rats
Rats, Sprague-Dawley
Receptors, Glucocorticoid / drug effects*
Receptors, Glucocorticoid / genetics
Response Elements
Structure-Activity Relationship
Transcription Factor AP-1 / genetics
Transcription Factor AP-1 / metabolism
Transcription, Genetic / drug effects

Substances

10-methoxy-5-(2-propenyl)-2,5-dihydro-2,2,4-trimethyl-1H-(1)benzopyrano(3,4-f)quinoline
5-cyclopentyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-1H-(1)benzopyrano(3,4-f)quinioline
Benzopyrans
E-Selectin
NF-kappa B
Quinolines
Receptors, Glucocorticoid
Transcription Factor AP-1
Carrageenan
Luciferases