Discovery of biaryl carboxylamides as potent RORγ inverse agonists. Issue 15 (1st August 2015)

• Record Type: Journal Article
• Authors: Chao, Jianhua; Enyedy, Istvan; Van Vloten, Kurt; Marcotte, Douglas; Guertin, Kevin; Hutchings, Richard; Powell, Noel; Jones, Howard; Bohnert, Tonika; Peng, Chi-Chi; Silvian, Laura; Hong, Victor Sukbong; Little, Kevin; Banerjee, Daliya; Peng, Liaomin; Taveras, Arthur; Viney, Joanne L.; Fontenot, Jason
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 15(2015)
• Page Start: 2991
• Page End: 2997
• Publication Date: 2015-08-01
• Subjects: Retinoid-related orphan receptor gamma t -- RORγt -- Th-17 -- IL-17 -- Biaryl carboxylamides; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.05.026
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: RORγt is a pivotal regulator of a pro-inflammatory gene expression program implicated in the pathology of several major human immune-mediated diseases. Evidence from mouse models demonstrates that genetic or pharmacological inhibition of RORγ activity can block the production of pathogenic cytokines, including IL-17, and convey therapeutic benefit. We have identified and developed a biaryl-carboxylamide series of RORγ inverse agonists via a structure based design approach. Co-crystal structures of compounds16 and48 supported the design approach and confirmed the key interactions with RORγ protein; the hydrogen bonding with His479 was key to the significant improvement in inverse agonist effect. The results have shown this is a class of potent and selective RORγ inverse agonists, with demonstrated oral bioavailability in rodents.