Glucocorticoid Receptor Modulators Informed by Crystallography Lead to a New Rationale for Receptor Selectivity, Function, and Implications for Structure-Based Design

• Published in: Journal of medicinal chemistry Vol. 57; no. 3; pp. 849 - 860
• Main Authors: Carson, Matthew W, Luz, John G, Suen, Chen, Montrose, Chahrzad, Zink, Richard, Ruan, Xiaoping, Cheng, Christine, Cole, Harlan, Adrian, Mary D, Kohlman, Dan T, Mabry, Thomas, Snyder, Nancy, Condon, Brad, Maletic, Milan, Clawson, David, Pustilnik, Anna, Coghlan, Michael J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.02.2014; Amer Chemical Soc; American Chemical Society (ACS)
• Subjects: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Arthritis, Experimental - chemically induced; Arthritis, Experimental - drug therapy; Benzoxepins - chemistry; Benzoxepins - pharmacokinetics; Benzoxepins - pharmacology; Binding Sites; Carrageenan; Cell Line; Chemistry, Medicinal; Chronic Disease; Collagen; Crystallography, X-Ray; Drug Design; Edema - chemically induced; Edema - drug therapy; Humans; Inflammation - drug therapy; Life Sciences & Biomedicine; Ligands; Male; Models, Molecular; Molecular Conformation; Pharmacology & Pharmacy; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid - chemistry; Receptors, Glucocorticoid - metabolism; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonamides - pharmacokinetics; Sulfonamides - pharmacology; TRANSREPRESSION; TETRASUBSTITUTED EXOCYCLIC ALKENES; IN-VITRO; TRANSACTIVATION; ANTAGONISM; LIGAND-BINDING DOMAIN; SEPARATION; RAY CRYSTAL-STRUCTURE; AGONIST; DIBENZOXAPINE
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm401616g

The structural basis of the pharmacology enabling the use of glucocorticoids as reliable treatments for inflammation and autoimmune diseases has been augmented with a new group of glucocorticoid receptor (GR) ligands. Compound 10, the archetype of a new family of dibenzoxepane and dibenzosuberane su...