Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists

James E. Sheppeck, John L. Gilmore, Hai Yun Xiao, T. G.Murali Dhar, David Nirschl, Arthur M. Doweyko, Jack S. Sack, Martin J. Corbett, Mary F. Malley, Jack Z. Gougoutas, Lorraine McKay, Mark D. Cunningham, Sium F. Habte, John H. Dodd, Steven G. Nadler, John E. Somerville, Joel C. Barrish

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)5442-5447
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number19
DOIs
StatePublished - Oct 1 2013

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Sheppeck, J. E., Gilmore, J. L., Xiao, H. Y., Dhar, T. G. M., Nirschl, D., Doweyko, A. M., Sack, J. S., Corbett, M. J., Malley, M. F., Gougoutas, J. Z., McKay, L., Cunningham, M. D., Habte, S. F., Dodd, J. H., Nadler, S. G., Somerville, J. E., & Barrish, J. C. (2013). Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists. Bioorganic and Medicinal Chemistry Letters, 23(19), 5442-5447. https://doi.org/10.1016/j.bmcl.2013.06.089