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 1a, an analogue of the known piperazine RORγt inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analogue 3a was found to be a potent RORγt inverse agonist. Structure-activity relationship studies on 3a, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analogue, 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-induced cytokine expression model revealed its robust and dose-dependent inhibitory effect on IL-17A production.

中文翻译：

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发现[1,2,4]三唑并[1,5-a]吡啶衍生物为强效和口服生物利用的RORγt反向激动剂。

视黄酸受体相关的孤儿核受体γt（RORγt）是一种有前途的治疗靶点，是与牛皮癣发病相关的基因的主要转录因子，例如白介素（IL）-17A，IL-22和IL-23R。基于RORγt与1a的X射线共晶体结构，设计并合成了已知的哌嗪RORγt逆激动剂1的类似物，并合成了1的三唑并吡啶衍生物，发现类似物3a是有效的RORγt逆激动剂。对3a的构效关系研究，专注于其代谢不稳定的环戊基环和中央哌嗪核心的治疗，导致了一个新的类似物，即6-甲基-N-（7-甲基-8-（（（2S， 4S）-2-甲基-1-（4,4,4-三氟-3-（三氟甲基）丁酰基）哌啶-4-基）氧基）[1,2,4]三唑[1,5-a]吡啶- 6-基）烟酰胺（5a），具有很强的RORγt抑制活性和良好的药代动力学特征。此外，在人全血分析和小鼠IL-18 / 23诱导的细胞因子表达模型中对5a的体外和体内评估显示出其对IL-17A产生的强大且剂量依赖性的抑制作用。