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.
authors: Ironwood Pharmaceuticals, Cambridge, MA 02142, United States. jim.sheppeck@bms.com
authors: James E
authors: JE
authors: Sheppeck
authors: John L
authors: JL
authors: Gilmore
authors: Hai-Yun
authors: HY
authors: Xiao
authors: T G Murali
authors: TG
authors: Dhar
authors: David
authors: D
authors: Nirschl
authors: Arthur M
authors: AM
authors: Doweyko
authors: Jack S
authors: JS
authors: Sack
authors: Martin J
authors: MJ
authors: Corbett
authors: Mary F
authors: MF
authors: Malley
authors: Jack Z
authors: JZ
authors: Gougoutas
authors: Lorraine
authors: L
authors: Mckay
authors: Mark D
authors: MD
authors: Cunningham
authors: Sium F
authors: SF
authors: Habte
authors: John H
authors: JH
authors: Dodd
authors: Steven G
authors: SG
authors: Nadler
authors: John E
authors: JE
authors: Somerville
authors: Joel C
authors: JC
authors: Barrish
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D007191:Indazoles; D011965:Receptors, Glucocorticoid; D013256:Steroids
keywords: Dissociated GR inhibitors; GR agonist; Glucocortocoid receptor