A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration.

中文翻译：

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口服有效的RORγt反向激动剂的发现，第1部分：鉴定新型苯基甘氨酰胺作为铅支架

通过优化高通量筛选命中率1，发现了一系列新的苯基甘氨酰胺作为视黄酸受体相关的孤儿受体-γt（RORγt）反向激动剂。（R）-N-（2-（（3,5-二氟-4-（三甲基甲硅烷基）苯基）氨基）-1-（4-甲氧基苯基）-2-氧乙基）-3-羟基-N-甲基异恶唑-5-羧酰胺（22）被确定为这些化合物中最好的化合物之一。与其他核受体相比，它具有更高的亚型选择性和特异性，并且在口服给药后在小鼠PD（药效学）模型中具有体内抑制RORγt转录活性的能力。