Discovery Of 6-Oxo-4-Phenyl-Hexanoic Acid Derivatives As Ror Gamma T Inverse Agonists Showing Favorable Adme Profile

The retinoic acid receptor-related orphan nuclear receptor gamma t (ROR gamma t), which is a promising therapeutic target for immune diseases, is a major transcription factor of genes related to psoriasis pathogenesis, such as interleukin (IL)-17A, IL-22, and IL-23R. Inspired by the co-crystal structure of ROR gamma t, a 6-oxo-4-phenyl-hexanoic acid derivative 6a was designed, synthesized, and identified as a ligand of ROR gamma t. The structure-activity relationship (SAR) studies in 6a, which focus on the improvement of its membrane permeability profile by introducing chlorine atoms, led to finding 12a, which has a potent ROR gamma t inhibitory activity and a favorable pharmacokinetic profile.