239066-73-0Relevant articles and documents
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
Elmore,Miner,Jacobson,Wilcox,Lane,Coghlan,Anderson,Pratt,Green,Wang,Stashko,Lin,Tyree
, p. 4481 - 4491 (2001)
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 ED50 = 1.7 mg/kg as compared to 1.2 mg/kg for prednisolone in the Sephadex-induced pulmonary eosinophilia model and an ED50 = 15 mg/kg vs 4 mg/kg for prednisolone in the carrageenan-induced paw edema model.
Synthesis and radiopharmacological characterization of [11C]AL-438 as a nonsteroidal ligand for imaging brain glucocorticoid receptors
Wuest, Frank,Kniess, Torsten,Bergmann, Ralf,Henry, Brian,Pietzsch, Jens
, p. 4035 - 4039 (2007)
The radiosynthesis and the radiopharmacological characterization of [11C]AL-438 as a nonsteroidal ligand for the glucocorticoid receptor (GR) is described. Radiolabeling of the corresponding desmethyl precursor 10 with [11C]MeI gave [11C]AL-438 in decay-corrected radiochemical yields of 30 ± 4% (based upon [11C]CO2) within 35 min at a specific radioactivity of 10-15 GBq/μmol at the end-of-synthesis. The radiopharmacological evaluation of [11C]AL-438 involved biodistribution and small animal PET imaging in rats, and autoradiography studies using rat brain sections. Biodistribution studies were performed in male Wistar rats and demonstrated high radioactivity uptake in pituitary and brain. However, the inability of high dose corticosterone to block binding would suggest that the radioactivity accumulation in the brain was not receptor-mediated.
Differentiation of in vitro transcriptional repression and activation profiles of selective glucocorticoid modulators
Elmore, Steven W.,Pratt, John K.,Coghlan, Michael J.,Mao, Yue,Green, Brian E.,Anderson, David D.,Stashko, Michael A.,Lin, Chun W.,Falls, Douglas,Nakane, Masaki,Miller, Loan,Tyree, Curtis M.,Miner, Jeffrey N.,Lane, Ben
, p. 1721 - 1727 (2007/10/03)
The SAR at C-5 of the 10-methoxy-2,2,4-trimethylbenzopyrano[3,4-f] quinoline core leading to identification of (-) anti 1-methylcyclohexen-3-yl as the optimum substituent that imparts minimal GR mediated in vitro transcriptional activation while maintaining full transcriptional repression is described. The in vitro profile of these candidates in human cell assays relevant to the therapeutic window of glucocorticoid modulators is outlined.
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-lh-[1]benzopyrano[3,4-f]quinolines
Kym, Philip R.,Kort, Michael E.,Coghlan, Michael J.,Moore, Jimmie L.,Tang, Rui,Ratajczyk, James D.,Larson, Daniel P.,Elmore, Steven W.,Pratt, John K.,Stashko, Michael A.,Douglass Falls,Lin, Chun W.,Nakane, Masake,Miller, Loan,Tyree, Curtis M.,Miner, Jeffery N.,Jacobson, Peer B.,Wilcox, Denise M.,Nguyen, Phong,Lane, Benjamin C.
, p. 1016 - 1030 (2007/10/03)
The preparation and characterization of a series of C-10 substituted 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines as a novel class of selective ligands for the glucocorticoid receptor is described. Substitution at the C-10 positi
A practical and scaleable synthesis of A-224817.0, a novel nonsteroidal ligand for the glucocorticoid receptor
Ku, Yi-Yin,Grieme, Tim,Raje, Prasad,Sharma, Padam,Morton, Howard E.,Rozema, Mike,King, Steve A.
, p. 3238 - 3240 (2007/10/03)
A practical and scaleable synthesis of a novel nonsteroidal ligand for the glucocorticoid receptor A-224817.0 1A is described. The synthesis proceeds in seven steps starting from 1,3-dimethoxybenzene. The biaryl intermediate 5 was prepared by an optimized
Glucocortiocoid-selective antinflammatory agents
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, (2008/06/13)
Compounds having Formula I are useful for partially or fully antagonizing, repressing, agonizing, or modulating the glucocorticoid receptor and treating immune, autoimmune and inflammatory diseases in a mammal. Also disclosed are pharmaceutical compositions comprising compounds of Formula I and methods of inhibiting immune or autoimmune diseases in a mammal.
