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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Sep 15

PMID 36105346

Authors

Ashley M Lato

Susan J Burke

Maggie P Ducote

Brandon J Kennedy

J Jason Collier

Shawn R Campagna

Affiliations

Soon will be listed here.

Abstract

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 isomers with an upward OH moiety were ∼70% more active on average than the 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.

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