Discovery of indazole ethers as novel, potent, non-steroidal glucocorticoid receptor modulators.
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.
Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 43183, Sweden. Electronic address: martin.hemmerling@astrazeneca.com.
Martin
M
Hemmerling
Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, Sweden.
Karl
K
Edman
Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 43183, Sweden.
Matti
M
Lepistö
Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 43183, Sweden.
Anders
A
Eriksson
AstraZeneca R&D Lund, Scheelevägen 1, Lund 22187, Sweden.
Svetlana
S
Ivanova
AstraZeneca R&D Lund, Scheelevägen 1, Lund 22187, Sweden.
Jan
J
Dahmén
Medicinal Chemistry Berlin, Candidate Generation & External Innovation, Drug Discovery, Bayer Pharma AG, Berlin 13353, Germany.
Hartmut
H
Rehwinkel
Medicinal Chemistry Berlin, Candidate Generation & External Innovation, Drug Discovery, Bayer Pharma AG, Berlin 13353, Germany.
Markus
M
Berger
Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 43183, Sweden.
Ramon
R
Hendrickx
Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 43183, Sweden.
Matthew
M
Dearman
Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 43183, Sweden.
Tina Jellesmark
TJ
Jensen
Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, Sweden.
Lisa
L
Wissler
Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 43183, Sweden.
Thomas
T
Hansson
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004987:Ethers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D007596:Joints / Q000187:drug effects / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D062105:Molecular Docking Simulation; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004987:Ethers; D007191:Indazoles; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha
Anti-inflammatory activity; Glucocorticoid receptor modulators; Indazoles; Non-steroidal glucocorticoid