title: Discovery of new selective glucocorticoid receptor agonist leads.
abstract: We report on the discovery of two new lead series for the development of glucocorticoid receptor agonists. Firstly, the discovery of tetrahydronaphthalenes led to metabolically stable and dissociated compounds. Their binding mode to the glucocorticoid receptor could be elucidated through an X-ray structure. Closer inspection into the reaction path and analyses of side products revealed a new amino alcohol series also addressing the glucocorticoid receptor and demonstrating strong anti-inflammatory activity in vitro.
authors.affiliation: Medicinal Chemistry Berlin, Candidate Generation & External Innovation, Drug Discovery, Bayer Pharma AG, D-13353 Berlin, Germany. Electronic address: markus.berger@bayer.com.
authors.forename: Markus
authors.initials: M
authors.lastname: Berger
authors.affiliation: Medicinal Chemistry Berlin, Candidate Generation & External Innovation, Drug Discovery, Bayer Pharma AG, D-13353 Berlin, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Rehwinkel
authors.affiliation: Medicinal Chemistry Berlin, Candidate Generation & External Innovation, Drug Discovery, Bayer Pharma AG, D-13353 Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Schmees
authors.affiliation: Gynecological Therapies Berlin, Global Therapeutic Research, Drug Discovery, Bayer Pharma AG, D-13353 Berlin, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Schäcke
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Edman
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wissler
authors.affiliation: Research Pharmacokinetics, Early Development, Drug Discovery, Bayer Pharma AG, D-13353 Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reichel
authors.affiliation: Global External Innovation & Alliances, Candidate Generation & External Innovation, Drug Discovery, Bayer Pharma AG, D-13353 Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Jaroch
mesh_terms: D000605:Amino Alcohols / Q000737:chemistry; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D017930:Genes, Reporter; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000605:Amino Alcohols; D000893:Anti-Inflammatory Agents; D011965:Receptors, Glucocorticoid; D013764:Tetrahydronaphthalenes
keywords: Amino alcohol; Glucocorticoid; SEGRA; Tetrahydronaphthalene; Transactivation; Transrepression