Abstract
The retinoid-related orphan receptor gamma-t (RORγt), a member of the nuclear receptor superfamily, functions as a ligand-dependent transcription factor. As a pivotal modulator in the development and functionality of T-helper 17 (Th17) cells, RORγt plays a crucial role in immune response regulation. Inverse agonists targeting RORγt demonstrate significant potential in modulating Th17 cell activity, offering a promising avenue for the development of therapeutics aimed at treating autoimmune diseases associated with Th17 dysregulation. GSK2981278 is a potent RORγt inverse agonist, but a drawback of GSK2981278 is its low pharmacokinetic profile, leading to a clinical failure. We have explored detailed structure–activity relationship of GSK2981278 trying to improve metabolic stability while maintaining RORγt activity. As a result, a novel series of sulfonamide derivatives was discovered as potent RORγt inverse agonists with improved drug-like properties. b14 had greatly improved In Vitro metabolic stability (T1/2 = 36.2 min) compared to GSK2981278 (T1/2 = 0.8 min). Oral dosing of compound b14 resulted in a dose-dependent suppression of IL-17A cytokine levels within a murine model of imiquimod-induced skin inflammation, underscoring its potential as a therapeutic intervention.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
