Discovery of [1,2,4]Triazolo[1,5-a]pyridine Derivatives as Potent and Orally Bioavailable RORγt Inverse Agonists

The retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. Based on the X-ray cocrystal structure of RORγt with 1a, an analog of a known piperazine RORγt inverse agonist (1), triazolopyridine derivatives of 1 were designed and synthesized, indicating analog 3a as a potent RORγt inverse agonist. The structure-activity relationships (SAR) studies in 3a, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analog, namely 6-methyl-N-(7-methyl-8-(((2S,4S)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)butanoyl)piperidin-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong RORγt inhibitory activity and a favorable pharmacokinetic profile. Moreover, the in vitro and in vivo evaluation of 5a in a human whole-blood assay and a mouse IL-18/23-in...