The discovery of potent and selective non-steroidal glucocorticoid receptor modulators, suitable for inhalation

The discovery of potent and selective non-steroidal glucocorticoid receptor modulators, suitable for inhalation

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. Furth...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2014-06, Vol.24 (11), p.2571-2577
Hauptverfasser: Edman, Karl, Ahlgren, Ragnhild, Bengtsson, Malena, Bladh, Håkan, Bäckström, Stefan, Dahmén, Jan, Henriksson, Krister, Hillertz, Per, Hulikal, Vijakumar, Jerre, Anders, Kinchin, Liz, Kåse, Charlotte, Lepistö, Matti, Mile, Irene, Nilsson, Stinabritt, Smailagic, Amir, Taylor, John, Tjörnebo, Ann, Wissler, Lisa, Hansson, Thomas
Format: Artikel
Sprache:eng
Schlagworte:
Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal - chemistry
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Discovery
Glucocorticoid receptor
High-Throughput Screening Assays
Humans
Indazoles
Inhalation
Ligands
Models, Molecular
Molecular Structure
Non-steroidal selective glucocorticoid receptor modulators
Receptors, Glucocorticoid - antagonists & inhibitors
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
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Zusammenfassung: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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2014.03.070