Format

Send to

Choose Destination
Bioorg Med Chem Lett. 2016 Dec 1;26(23):5741-5748. doi: 10.1016/j.bmcl.2016.10.052. Epub 2016 Oct 19.

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

Author information

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.

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

PMID:
27810243
DOI:
10.1016/j.bmcl.2016.10.052
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center