934986-87-5Relevant academic research and scientific papers
Discovery of indazole ethers as novel, potent, non-steroidal glucocorticoid receptor modulators
Hemmerling, Martin,Edman, Karl,Lepist?, Matti,Eriksson, Anders,Ivanova, Svetlana,Dahmén, Jan,Rehwinkel, Hartmut,Berger, Markus,Hendrickx, Ramon,Dearman, Matthew,Jensen, Tina Jellesmark,Wissler, Lisa,Hansson, Thomas
supporting information, p. 5741 - 5748 (2016/11/28)
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.
The discovery of potent and selective non-steroidal glucocorticoid receptor modulators, suitable for inhalation
Edman, Karl,Ahlgren, Ragnhild,Bengtsson, Malena,Bladh, Hakan,Baeckstroem, Stefan,Dahmen, Jan,Henriksson, Krister,Hillertz, Per,Hulikal, Vijakumar,Jerre, Anders,Kinchin, Liz,Kase, Charlotte,Lepistoe, Matti,Mile, Irene,Nilsson, Stinabritt,Smailagic, Amir,Taylor, John,Tjoernebo, Ann,Wissler, Lisa,Hansson, Thomas
supporting information, p. 2571 - 2577 (2014/05/20)
We report the discovery of highly potent and selective non-steroidal glucocorticoid receptor modulators with PK properties suitable for inhalation. A high throughput screen of the AstraZeneca compound collection identified sulfonamide 3 as a potent non-steroidal glucocorticoid receptor ligand. Further optimization of this lead generated indazoles 30 and 48 that were progressed to characterization in in vivo models. X-ray crystallography was used to gain further insight into the binding mode of selected ligands.
NOVEL BICYCLIC SULFONAMIDES FOR USE AS GLUCOCORTICOID RECEPTOR MODULATORS IN THE TREATMENT OF INFLAMMATORY DISEASES
-
Page/Page column 26, (2008/06/13)
Compounds of formula (I): or a pharmaceutically acceptable salt thereof; compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating the glucocorticoid receptor in a warm blooded animal).
