Discovery of (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidines as novel RORγt inverse agonists

A novel series of cis-3,4-diphenylpyrrolidines were designed as ROR gamma t inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesis and structure-activity relationship (SAR) study established (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydro-xyprop-2-yl)phenyl)pyrrolidine as the most effective scaffold. Subsequent SAR optimization led to identification of a piperidinyl carboxamide 31, which was potent against ROR gamma t (EC50 of 61 nM in an inverse agonist assay), selective relative to ROR alpha, RORj3, LXR alpha and LXRj3, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Y-max (46%) and emerged as a promising lead. The binding mode of the diphenylpyrrolidine series was established with an X-ray co-crystal structure of 10A/ROR gamma t.