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 Harold Dodd, Steven G. Nadler, John E. Somerville, Joel C. Barrish

Research output: Contribution to journalArticle

12 Citations (Scopus)

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

Fingerprint

Indazoles
Glucocorticoid Receptors
Cytoplasmic and Nuclear Receptors
Amides
Glucocorticoids
Assays
Crystal structure
X-Rays
X rays
Lead
In Vitro Techniques

All Science Journal Classification (ASJC) codes

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

Cite this

Sheppeck, J. E., Gilmore, J. L., Xiao, H. Y., Dhar, T. G. M., Nirschl, D., Doweyko, A. M., ... 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
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 Harold ; Nadler, Steven G. ; Somerville, John E. ; Barrish, Joel C. / Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists. In: Bioorganic and Medicinal Chemistry Letters. 2013 ; Vol. 23, No. 19. pp. 5442-5447.
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Sheppeck, JE, Gilmore, JL, Xiao, HY, Dhar, TGM, Nirschl, D, Doweyko, AM, Sack, JS, Corbett, MJ, Malley, MF, Gougoutas, JZ, McKay, L, Cunningham, MD, Habte, SF, Dodd, JH, Nadler, SG, Somerville, JE & Barrish, JC 2013, 'Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 19, pp. 5442-5447. https://doi.org/10.1016/j.bmcl.2013.06.089

Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists. / 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 Harold; Nadler, Steven G.; Somerville, John E.; Barrish, Joel C.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 19, 01.10.2013, p. 5442-5447.

Research output: Contribution to journalArticle

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AU - Sheppeck, James E.

AU - Gilmore, John L.

AU - Xiao, Hai Yun

AU - Dhar, T. G.Murali

AU - Nirschl, David

AU - Doweyko, Arthur M.

AU - Sack, Jack S.

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AU - Malley, Mary F.

AU - Gougoutas, Jack Z.

AU - McKay, Lorraine

AU - Cunningham, Mark D.

AU - Habte, Sium F.

AU - Dodd, John Harold

AU - Nadler, Steven G.

AU - Somerville, John E.

AU - Barrish, Joel C.

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