Structure guided design of 5-arylindazole glucocorticoid receptor agonists and antagonists.

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Yates CM, Brown PJ, Stewart EL, Patten C, Austin RJ, Holt JA, Maglich JM, Angell DC, Sasse RZ, Taylor SJ, Uings IJ, Trump RP

Structure guided design of 5-arylindazole glucocorticoid receptor agonists and antagonists.

J Med Chem. 2010 Jun 10;53(11):4531-44. doi: 10.1021/jm100447c.

PubMed ID
20469868 [ View in PubMed
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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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
MifepristoneGlucocorticoid receptorIC 50 (nM)>10000N/AN/ADetails
MifepristoneGlucocorticoid receptorIC 50 (nM)6.31N/AN/ADetails
MifepristoneProgesterone receptorIC 50 (nM)7.94N/AN/ADetails