Novel glucocorticoids containing a 6,5-bicyclic core fused to a pyrazole ring: Synthesis, in vitro profile, molecular modeling studies, and in vivo experiments

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 12; pp. 3354 - 3361
• Main Authors: Thompson, Christopher F., Quraishi, Nazia, Ali, Amjad, Mosley, Ralph T., Tata, James R., Hammond, Milton L., Balkovec, James M., Einstein, Monica, Ge, Lan, Harris, Georgianna, Kelly, Terri M., Mazur, Paul, Pandit, Shilpa, Santoro, Joseph, Sitlani, Ayesha, Wang, Chuanlin, Williamson, Joanne, Miller, Douglas K., Yamin, Ting-ting D., Thompson, Chris M., O’Neill, Edward A., Zaller, Dennis, Forrest, Michael J., Carballo-Jane, Ester, Luell, Silvi
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.06.2007; Elsevier
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Biological and medical sciences; Bridged Bicyclo Compounds - chemistry; Cell Line, Tumor; Dissociation; Glucocorticoid; Glucocorticoids - chemistry; Hormones. Endocrine system; Humans; Inflammation; Ligands; Medical sciences; Mice; Models, Chemical; Models, Molecular; Pharmacology. Drug treatments; Pyrazoles - chemistry; Receptors, Glucocorticoid - drug effects; Receptors, Glucocorticoid - metabolism; Structure-Activity Relationship; Transactivation; Transrepression; Inflammation; Dissociation; Transrepression; Glucocorticoid; Transactivation; Steroid; Ligand; Metabolite; Molecular interaction; Modeling; Benzothiophene derivatives; Structure activity relation; Tertiary alcohol; Molecular model; Glucocorticoid receptor; Chemical synthesis; Corticosteroid; Rodentia; In vitro; In vivo; Vertebrata; Biological fixation; Mammalia; Mouse; Animal; Organic fluorine compounds; Conformation; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.03.103

Compounds containing the depicted core were synthesized. These compounds were evaluated for binding to the glucocorticoid receptor in cell based transactivation and transrepression assays. Molecular modeling and in vivo data are also provided. Chemistry was developed to synthesize the title series of compounds. The ability of these novel ligands to bind to the glucocorticoid receptor was investigated. These compounds were also tested in a series of functional assays and some were found to display the profile of a dissociated glucocorticoid. The SAR of the 6,5-bicyclic series differed markedly from the previously reported 6,6-series. Molecular modeling studies were employed to understand the conformational differences between the two series of compounds, which may explain their divergent activity. Two compounds were profiled in vivo and shown to reduce inflammation in a mouse model. An active metabolite is suspected in one case.