Discovery of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists

A novel series of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as ROR gamma t inverse agonists was discovered. Binding mode analysis of a ROR gamma t partial agonist (2c) revealed by co-crystal structure in ROR gamma t LBD suggests that the inverse agonists do not directly interfere with the interaction between H12 and the ROR gamma t LBD. Detailed SAR exploration led to identification of potent ROR gamma t inverse agonists such as 3m with a pIC(50) of 8.0. Selected compounds in the series showed reasonable activity in Th17 cell differentiation assay as well as low intrinsic clearance in mouse liver microsomes. (C) 2015 Elsevier Ltd. All rights reserved.