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

Abstract

The retinoic acid receptor-related orphan nuclear receptor γt (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. On the basis of the X-ray cocrystal structure of RORγt with <b>1a</b>, an analogue of the known piperazine RORγt inverse agonist <b>1</b>, triazolopyridine derivatives of <b>1</b> were designed and synthesized, and analogue <b>3a</b> was found to be a potent RORγt inverse agonist. Structure-activity relationship studies on <b>3a</b>, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analogue, namely, 6-methyl-<i>N</i>-(7-methyl-8-(((2<i>S</i>,4<i>S</i>)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)butanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-<i>a</i>]pyridin-6-yl)nicotinamide (<b>5a</b>), which exhibited strong RORγt inhibitory activity and a favorable pharmacokinetic profile. Moreover, the <i>in vitro</i> and <i>in vivo</i> evaluation of <b>5a</b> in a human whole-blood assay and a mouse IL-18/23-induced cytokine expression model revealed its robust and dose-dependent inhibitory effect on IL-17A production.