2. Academic Validation
  3. Discovery of indazole ethers as novel, potent, non-steroidal glucocorticoid receptor modulators

Discovery of indazole ethers as novel, potent, non-steroidal glucocorticoid receptor modulators

  • Bioorg Med Chem Lett. 2016 Dec 1;26(23):5741-5748. doi: 10.1016/j.bmcl.2016.10.052.
Martin Hemmerling 1,  Karl Edman 2,  Matti Lepistö 3,  Anders Eriksson 3,  Svetlana Ivanova 4,  Jan Dahmén 4,  Hartmut Rehwinkel 5,  Markus Berger 5,  Ramon Hendrickx 3,  Matthew Dearman 3,  Tina Jellesmark Jensen 3,  Lisa Wissler 2,  Thomas Hansson 3
Affiliations

Affiliations

  • 1 Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 43183, Sweden. Electronic address: martin.hemmerling@astrazeneca.com.
  • 2 Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, Sweden.
  • 3 Respiratory, Inflammation & Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal 43183, Sweden.
  • 4 AstraZeneca R&D Lund, Scheelevägen 1, Lund 22187, Sweden.
  • 5 Medicinal Chemistry Berlin, Candidate Generation & External Innovation, Drug Discovery, Bayer Pharma AG, Berlin 13353, Germany.
PMID: 27810243 DOI: 10.1016/j.bmcl.2016.10.052
Abstract

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.

Keywords

Anti-inflammatory activity; Glucocorticoid receptor modulators; Indazoles; Non-steroidal glucocorticoid.

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