Novel ketal ligands for the glucocorticoid receptor: in vitro and in vivo activity

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 11; pp. 2926 - 2931
• Main Authors: Smith, Cameron J., Ali, Amjad, Balkovec, James M., Graham, Donald W., Hammond, Milton L., Patel, Gool F., Rouen, Gregory P., Smith, Scott K., Tata, James R., Einstein, Monica, Ge, Lan, Harris, Georgianna S., Kelly, Theresa M., Mazur, Paul, Thompson, Chris M., Wang, Chuanlin F., Williamson, Joanne M., Miller, Douglas K., Pandit, Shilpa, Santoro, Joseph C., Sitlani, Ayesha, Yamin, Ting-ting D., O’Neill, Edward A., Zaller, Dennis M., Carballo-Jane, Ester, Forrest, Michael J., Luell, Silvi
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 02.06.2005; Elsevier
• Subjects: Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cells, Cultured; Dissociation; Glucocorticoid; Humans; In Vitro Techniques; Inflammation; Ligands; Medical sciences; Mice; Pharmacology. Drug treatments; Receptors, Glucocorticoid - metabolism; Transactivation; Transrepression; Inflammation; Dissociation; Transrepression; Glucocorticoid; Transactivation; Partial agonist; Intravenous administration; Selectivity; Interleukin 6; Acetal; Structure activity relation; Glucocorticoid receptor; Inhibition; Non steroid compound; Tumor necrosis factor α; Oxygen nitrogen heterocycle; Human; Ring size; Rodentia; Antiinflammatory agent; Benzene derivatives; Cytokine; Oral administration; Bioavailability; Tetracyclic compound; In vitro; Spiran; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Affinity; Fluorine Organic compounds; Pharmacokinetics; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.03.027

Compound 28 was found to have a dissociated glucocorticoid profile in vitro and produced a dose-dependent anti-inflammatory response in an in vivo mouse model. A novel series of selective ligands for the human glucocorticoid receptor is described. Structure–activity studies focused on variation of B-ring size, ketal ring size, and ketal substitution. These analogs were found to be potent and selective ligands for GR and have partial agonist profiles in functional assays for transactivation (TAT, GS) and transrepression (IL-6). Of these compounds, 27, 28, and 35 were evaluated further in a mouse LPS-induced TNF-α secretion model. Compound 28 had an ED 50 of 14.1 mg/kg compared with 0.5 mg/kg for prednisolone in the same assay.