Identification and biological evaluation of thiazole-based inverse agonists of RORγt.
The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORγt) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORγt lies at the core of this pathway and represents an attractive opportunity for intervention with a small molecule. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of RORγt drug discovery. We describe the discovery and evaluation of a new class of potent and selective RORγt inverse agonists based on a thiazole core. Acid analog 1j demonstrated oral bioavailability in rats and was potent in a human whole blood assay, suggesting potential utility in treating autoimmune and inflammatory diseases such as psoriasis. X-ray crystallographic data helped to elucidate the molecular mechanism for RORγt inhibition with this series.
['Gege|Christian|C|', 'Cummings|Maxwell D|MD|', 'Albers|Michael|M|', 'Kinzel|Olaf|O|', 'Kleymann|Gerald|G|', 'Schlüter|Thomas|T|', 'Steeneck|Christoph|C|', 'Nelen|Marina I|MI|', 'Milligan|Cindy|C|', 'Spurlino|John|J|', 'Xue|Xiaohua|X|', 'Leonard|Kristi|K|', 'Edwards|James P|JP|', 'Fourie|Anne|A|', 'Goldberg|Steven D|SD|', 'Hoffmann|Thomas|T|']
D000818:Animals D018360:Crystallography, X-Ray D006801:Humans D008958:Models, Molecular D015394:Molecular Structure D051381:Rats D018168:Receptors, Retinoic Acid D013329:Structure-Activity Relationship D013844:Thiazoles
Inverse agonist RORγt Thiazole RORc Retinoid-related orphan receptor gamma t