Discovery of biaryl carboxylamides as potent RORγ inverse agonists
作者： Jianhua Chao , Istvan Enyedy , Kurt Van Vloten , Douglas Marcotte , Kevin Guertin
DOI: 10.1016/J.BMCL.2015.05.026
关键词:
摘要: RORγt is a pivotal regulator of pro-inflammatory gene expression program implicated in the pathology several major human immune-mediated diseases. Evidence from mouse models demonstrates that genetic or pharmacological inhibition RORγ activity can block production pathogenic cytokines, including IL-17, and convey therapeutic benefit. We have identified developed biaryl-carboxylamide series inverse agonists via structure based design approach. Co-crystal structures compounds 16 48 supported approach confirmed key interactions with protein; hydrogen bonding His479 was to significant improvement agonist effect. The results shown this class potent selective agonists, demonstrated oral bioavailability rodents.
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