Stereoisomers of an Aryl Pyrazole Glucocorticoid Receptor Agonist Scaffold Elicit Differing Anti-inflammatory Responses

Glucocorticoids (GCs) are heavily prescribed to control inflammation in various human diseases; however, side effects associated with GCs are well documented and lead to serious metabolic and immunological complications with long-term use. The paradigm for GC function includes two well described mod...

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Veröffentlicht in:ACS medicinal chemistry letters Jg. 13; H. 9; S. 1493 - 1499
Hauptverfasser: Lato, Ashley M., Burke, Susan J., Ducote, Maggie P., Kennedy, Brandon J., Collier, J. Jason, Campagna, Shawn R.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: WASHINGTON Amer Chemical Soc 08.09.2022
Schlagworte:
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
Stereoisomers
Aryl pyrazole
DNA-BINDING
MECHANISM
LIGANDS
STEREOCHEMISTRY
Anti-inflammatory
Glucocorticoid
Molecular docking
ISSN:1948-5875, 1948-5875
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Zusammenfassung:Glucocorticoids (GCs) are heavily prescribed to control inflammation in various human diseases; however, side effects associated with GCs are well documented and lead to serious metabolic and immunological complications with long-term use. The paradigm for GC function includes two well described modes of activity: dimer formation of the glucocorticoid receptor (GR) promotes transactivation, while monomeric interaction with co-regulators promotes transrepression. Previously, a set of aryl pyrazole-derived glucocorticoid receptor agonists (APGRAs) with potency rivaling current commercially available glucocorticoids were described. In this study, a further series of existing and novel stereopure APGRAs were thoroughly examined for biological activity and evaluated for structure-activity relationships (SARs). The si isomers with an upward OH moiety were similar to 70% more active on average than the re isomers. Additionally, AP13 was found to elicit 79% transrepression of dexamethasone while eliciting less than half the transactivation response in 832/13 cells, a rat insulinoma cell line.
Bibliographie:ObjectType-Article-1
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ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.2c00299