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

doi:10.1016/j.bmcl.2013.06.089

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

Chemistry

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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 language	English (US)
Pages (from-to)	5442-5447
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	19
DOIs	https://doi.org/10.1016/j.bmcl.2013.06.089
State	Published - Oct 1 2013

All Science Journal Classification (ASJC) codes

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

Access to Document

10.1016/j.bmcl.2013.06.089

Cite this

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

@article{74cb0c33804d41b58651077d7c98f0fb,

title = "Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists",

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.",

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

year = "2013",

month = oct,

day = "1",

doi = "10.1016/j.bmcl.2013.06.089",

language = "English (US)",

volume = "23",

pages = "5442--5447",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

number = "19",

}

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

TY - JOUR

T1 - Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists

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.

AU - Corbett, Martin J.

AU - Malley, Mary F.

AU - Gougoutas, Jack Z.

AU - McKay, Lorraine

AU - Cunningham, Mark D.

AU - Habte, Sium F.

AU - Dodd, John H.

AU - Nadler, Steven G.

AU - Somerville, John E.

AU - Barrish, Joel C.

PY - 2013/10/1

Y1 - 2013/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84883487140&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84883487140&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2013.06.089

DO - 10.1016/j.bmcl.2013.06.089

M3 - Article

C2 - 23953070

AN - SCOPUS:84883487140

SN - 0960-894X

VL - 23

SP - 5442

EP - 5447

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 19

ER -

Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this