Discovery of indazole ethers as novel, potent, non-steroidal glucocorticoid receptor modulators. Issue 23 (1st December 2016)

• Record Type: Journal Article
• Authors: Hemmerling, Martin; Edman, Karl; Lepistö, Matti; Eriksson, Anders; Ivanova, Svetlana; Dahmén, Jan; Rehwinkel, Hartmut; Berger, Markus; Hendrickx, Ramon; Dearman, Matthew; Jensen, Tina Jellesmark; Wissler, Lisa; Hansson, Thomas
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 23(2016)
• Page Start: 5741
• Page End: 5748
• Publication Date: 2016-12-01
• Subjects: Non-steroidal glucocorticoid -- Glucocorticoid receptor modulators -- Indazoles -- Anti-inflammatory activity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.10.052
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A structure-based design approach led to the identification of a novel class of indazole ether based, non-steroidal glucocorticoid receptor (GR) modulators. Several examples were identified that displayed cell potency in the picomolar range, inhibiting LPS-induced TNF-α release by primary peripheral blood mononuclear cells (PBMCs). Additionally, an improved steroid hormone receptor binding selectivity profile, compared to classical steroidal GR agonists, was demonstrated. The indazole ether core tolerated a broad range of substituents allowing for modulation of the physiochemical parameters. A small sub-set of indazole ethers, with pharmacokinetic properties suitable for oral administration, was investigated in a rat antigen-induced joint inflammation model and demonstrated excellent anti-inflammatory efficacy.