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

作者：Amjad Ali, Christopher F. Thompson, James M. Balkovec, Donald W. Graham, Milton L. Hammond, Nazia Quraishi, James R. Tata, Monica Einstein, Lan Ge, Georgianna Harris, Terri Kelly, Paul Mazur, Shilpa Pandit, Joseph C. Santoro, Ayesha Sitlani, Chuanlin Wang, Joanne M. Williamson, Douglas K. Miller, Chris M. Thompson, Dennis M. Zaller, Michael J. Forrest, Ester Carballo‐Jane, Silvi Luell · 发表于：Journal of Medicinal Chemistry · 年份：2004 · DOI：10.1021/jm030585i · 被引用次数：66 · 研究领域：Estrogen and related hormone effects、Synthesis and Biological Evaluation、Bioactive Compounds and Antitumor Agents

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.