Indole Glucocorticoid Receptor Antagonists Active in a Model of Dyslipidemia Act via a Unique Association with an Agonist Binding Site

Luz, John G.; Carson, Matthew W.; Condon, Bradley; Clawson, David; Pustilnik, Anna; Kohlman, Daniel T.; Barr, Robert J.; Bean, James S.; Dill, M. Joelle; Sindelar, Dana K.; Maletic, Milan; Coghlan, Michael J.

doi:10.1021/acs.jmedchem.5b00736

Title: Indole Glucocorticoid Receptor Antagonists Active in a Model of Dyslipidemia Act via a Unique Association with an Agonist Binding Site

Journal Article · Tue Jul 28 00:00:00 EDT 2015 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.5b00736· OSTI ID:1241054

Luz, John G. ^[1]; Carson, Matthew W. ^[2]; Condon, Bradley ^[1]; Clawson, David ^[2]; Pustilnik, Anna ^[1]; Kohlman, Daniel T. ^[2]; Barr, Robert J. ^[2]; Bean, James S. ^[2]; Dill, M. Joelle ^[2]; Sindelar, Dana K. ^[2]; Maletic, Milan ^[1]; Coghlan, Michael J. ^[2]

Eli Lilly Biotechnology Center, San Diego, CA (United States)
Lilly Research Labs, Indianapolis, IN (United States)

To further elucidate the structural activity correlation of glucocorticoid receptor (GR) antagonism, the crystal structure of the GR ligand-binding domain (GR LBD) complex with a nonsteroidal antagonist, compound 8, was determined. This novel indole sulfonamide shows in vitro activity comparable to known GR antagonists such as mifepristone, and notably, this molecule lowers LDL (–74%) and raises HDL (+73%) in a hamster model of dyslipidemia. Here, this is the first reported crystal structure of the GR LBD bound to a nonsteroidal antagonist, and this article provides additional elements for the design and pharmacology of clinically relevant nonsteroidal GR antagonists that may have greater selectivity and fewer side effects than their steroidal counterparts.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1241054

Journal Information:: Journal of Medicinal Chemistry, Vol. 58, Issue 16; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 26 works

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Title: Indole Glucocorticoid Receptor Antagonists Active in a Model of Dyslipidemia Act via a Unique Association with an Agonist Binding Site

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