title: The discovery of potent and selective non-steroidal glucocorticoid receptor modulators, suitable for inhalation.
abstract: 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.
authors.affiliation: Discovery Sciences, Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Edman
authors.affiliation: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors.forename: Ragnhild
authors.initials: R
authors.lastname: Ahlgren
authors.affiliation: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors.forename: Malena
authors.initials: M
authors.lastname: Bengtsson
authors.affiliation: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Bladh
authors.affiliation: Discovery Sciences, Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bäckström
authors.affiliation: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Dahmén
authors.affiliation: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors.forename: Krister
authors.initials: K
authors.lastname: Henriksson
authors.affiliation: Discovery Sciences, Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hillertz
authors.affiliation: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors.forename: Vijakumar
authors.initials: V
authors.lastname: Hulikal
authors.affiliation: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Jerre
authors.affiliation: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors.forename: Liz
authors.initials: L
authors.lastname: Kinchin
authors.affiliation: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kåse
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Matti
authors.initials: M
authors.lastname: Lepistö
authors.affiliation: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors.forename: Irene
authors.initials: I
authors.lastname: Mile
authors.affiliation: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors.forename: Stinabritt
authors.initials: S
authors.lastname: Nilsson
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Amir
authors.initials: A
authors.lastname: Smailagic
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Taylor
authors.affiliation: AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Tjörnebo
authors.affiliation: Discovery Sciences, Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wissler
authors.affiliation: Respiratory, Inflammation and Autoimmunity, Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. Electronic address: thomas.g.hansson@astrazeneca.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hansson
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008024:Ligands; D011965:Receptors, Glucocorticoid; D013449:Sulfonamides
keywords: Glucocorticoid receptor; Indazoles; Inhalation; Non-steroidal selective glucocorticoid receptor modulators