Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 19; pp. 5442 - 5447
• Main Authors: Sheppeck, James E., Gilmore, John L., Xiao, Hai-Yun, Dhar, T.G. Murali, Nirschl, David, Doweyko, Arthur M., Sack, Jack S., Corbett, Martin J., Malley, Mary F., Gougoutas, Jack Z., Mckay, Lorraine, Cunningham, Mark D., Habte, Sium F., Dodd, John H., Nadler, Steven G., Somerville, John E., Barrish, Joel C.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.10.2013; Elsevier
• Subjects: agonists; Amides - chemistry; Amides - pharmacology; Binding Sites; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; Dissociated GR inhibitors; Drug Discovery; glucocorticoid receptors; Glucocortocoid receptor; GR agonist; Humans; in vitro studies; Indazoles - chemistry; Indazoles - pharmacology; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Protein Binding - drug effects; Receptors, Glucocorticoid - agonists; Science & Technology; Steroids - chemistry; Steroids - pharmacology; Structure-Activity Relationship; X-radiation; Glucocortocoid receptor; Dissociated GR inhibitors; GR agonist; TRANSREPRESSION; DNA-BINDING; DESIGN; PYRAZOLES; MODULATORS; TRANSACTIVATION; LIGAND-BINDING DOMAIN; N-ARYLATION
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.06.089

Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.