Discovery and optimization of novel, non-steroidal glucocorticoid receptor modulators

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 17; pp. 4901 - 4905
• Main Authors: Ray, Nicholas C., Clark, Robin D., Clark, David E., Williams, Karen, Hickin, H.G., Crackett, Peter H., Dyke, Hazel J., Lockey, Peter M., Wong, Melanie, Devos, René, White, Anne, Belanoff, Joseph K.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.09.2007; Elsevier
• Subjects: Animals; Antagonist; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antidepressive Agents - chemical synthesis; Antidepressive Agents - pharmacology; Biological and medical sciences; Depression; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Glucocorticoid; Glucocorticoids - chemistry; Hormones. Endocrine system; Humans; Kinetics; Medical sciences; Models, Chemical; Molecular Conformation; Pharmacology. Drug treatments; Psychotic; Rats; Receptors, Glucocorticoid - metabolism; Receptors, Steroid - metabolism; Structure-Activity Relationship; Depression; Psychotic; Antagonist; Glucocorticoid; Mood disorder; Nitrogen heterocycle; Benzene derivatives; Virtual screening; In vitro; Structure activity relation; Piperidine derivatives; Glucocorticoid receptor; Affinity; Pyrimidine derivatives; Chemical synthesis; Non steroid compound; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.06.036

A virtual screening approach followed by lead optimization led to a series of compounds, exemplified by 12, that were potent, selective GR antagonists. A virtual screening approach comprising a 3-D similarity search based on known GR modulators was used to identify a novel series of non-steroidal glucocorticoid receptor (GR) antagonists. Optimization of the initial hit to provide potent compounds which exhibit good selectivity against other steroidal nuclear hormone receptors is described.