Novel N-Arylpyrazolo[3,2-c]-Based Ligands for the Glucocorticoid Receptor: Receptor Binding and in Vivo Activity

Citations Over TimeTop 10% of 2004 papers

Abstract

A novel series of selective ligands for the human glucocorticoid receptor (hGR) are described. Preliminary structure-activity relationships were focused on substitution at C-1 and indicated a preference for 3-, 4-, and 5-substituted aromatic and benzylic groups. The resulting analogues, e.g., 18 and 34, exhibited excellent affinity for hGR (IC(50) 1.9 nM and 2.8 nM, respectively) and an interesting partial agonist profile in functional assays of transactivation (tyrosine aminotransferase, TAT, and glutamine synthetase, GS) and transrepression (IL-6). The most potent compounds described in this study were the tertiary alcohol derivatives 21 and 25. These candidates showed highly efficacious IL-6 inhibition versus dexamethasone. The thiophenyl analogue 25 was evaluated in vivo in the mouse LPS challenge model and showed an ED(50) = 4.0 mg/kg, compared to 0.5 mg/kg for prednisolone in the same assay.

Related Papers

• → The role of the glucocorticoid receptor and its impact on steroid response in moderate-severe COVID-19 patients(2023)6 cited
• → Heterogeneity of Binding Sites for Glucocorticoid and the Glucocorticoid-Receptor Complex in Rat Livers(1984)1 cited
• [Medicinal activation and inhibition of function of glucocorticoid receptors as the basis for regulation of the glucocorticoid effect].(1994)
• → Giucocorticoid-Insensitive Bronchial Asthma(2008)
• Study on the Relationship Between Sensitivity to Glucocorticoid and Glucocorticoid Receptor Isoform in Patients with Idiopathic Thrombocytopenia Purpura(2007)