Document Report Card

ID: ALA1137074

Journal: J Med Chem

Title: Novel N-arylpyrazolo[3,2-c]-based ligands for the glucocorticoid receptor: receptor binding and in vivo activity.

Authors: Ali A, Thompson CF, Balkovec JM, Graham DW, Hammond ML, Quraishi N, Tata JR, Einstein M, Ge L, Harris G, Kelly TM, Mazur P, Pandit S, Santoro J, Sitlani A, Wang C, Williamson J, Miller DK, Thompson CM, Zaller DM, Forrest MJ, Carballo-Jane E, Luell S.

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.

CiteXplore: 15115388

DOI: 10.1021/jm030585i