title: Structure guided design of 5-arylindazole glucocorticoid receptor agonists and antagonists.
abstract: Glucocorticoid receptor (GR) agonists have been used for more than half a century as the most effective treatment of acute and chronic inflammatory conditions despite serious side effects that accompany their extended use that include glucose intolerance, muscle wasting, skin thinning, and osteoporosis. As a starting point for the identification of GR ligands with an improved therapeutic index, we wished to discover selective nonsteroidal GR agonists and antagonists with simplified structure compared to known GR ligands to serve as starting points for the optimization of dissociated GR modulators. To do so, we selected multiple chemical series by structure guided docking studies and evaluated GR agonist activity. From these efforts we identified 5-arylindazole compounds that showed moderate binding to the glucocorticoid receptor (GR) with clear opportunities for further development. Structure guided optimization was used to design arrays that led to potent GR agonists and antagonists. Several in vitro and in vivo experiments were utilized to demonstrate that GR agonist 23a (GSK9027) had a profile similar to that of a classical steroidal GR agonist.
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709-3398, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Yates
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Stewart
authors.forename: Christopher
authors.initials: C
authors.lastname: Patten
authors.forename: Robert J H
authors.initials: RJ
authors.lastname: Austin
authors.forename: Jason A
authors.initials: JA
authors.lastname: Holt
authors.forename: Jodi M
authors.initials: JM
authors.lastname: Maglich
authors.forename: Davina C
authors.initials: DC
authors.lastname: Angell
authors.forename: Rosemary Z
authors.initials: RZ
authors.lastname: Sasse
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Taylor
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Uings
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Trump
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D007191:Indazoles; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid