Structure guided design of 5-arylindazole glucocorticoid receptor agonists and antagonists.
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.
Yates
Christopher M
CM
Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709-3398, USA.
Brown
Peter J
PJ
Stewart
Eugene L
EL
Patten
Christopher
C
Austin
Robert J H
RJ
Holt
Jason A
JA
Maglich
Jodi M
JM
Angell
Davina C
DC
Sasse
Rosemary Z
RZ
Taylor
Simon J
SJ
Uings
Iain J
IJ
Trump
Ryan P
RP
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
D007191:Indazoles; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid