Bioorganic & Medicinal Chemistry
Wang, Y;Cai, W;Zhang, G;Yang, T;Liu, Q;Cheng, Y;Zhou, L;Ma, Y;Cheng, Z;Lu, S;Zhao, YG;Zhang, W;Xiang, Z;Wang, S;Yang, L;Wu, Q;Orband-Miller, LA;Xu, Y;Zhang, J;Gao, R;Huxdorf, M;Xiang, JN;Zhong, Z;Elliott, JD;Leung, S;Lin, X;
Novel series of N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (RORt) inhibitors. SAR studies of the RORt HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene ketone amide 9g with high binding affinity and inhibitory activity of Th17 cell differentiation. Compound 8h showed in vivo efficacy in both mouse experimental autoimmune encephalomyelitis (EAE) and collagen induced arthritis (CIA) models via oral administration.