The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment of autoimmune diseases. The nuclear hormone receptor RORγt is a master regulator of Th17 cells and affects the production of a host of cytokines, including IL-17A, IL-17F, IL-22, IL-26, and GM-CSF. Substantial interest has been spurred across both academia and industry to seek small molecules suitable for RORγt inhibition. A variety of RORγt inhibitors have been reported in the past few years, the majority of which are orthosteric binders. Here we disclose the discovery and optimization of a class of inhibitors, which bind differently to an allosteric binding pocket. Starting from a weakly active hit 1, a tool compound 14 was quickly identified that demonstrated superior potency, selectivity, and off-target profile. Further optimization focused on improving metabolic stability. Replacing the benzoic acid moiety with piperidinyl carboxylate, modifying the 4-aza-indazole core in 14 to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery of 25, which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing.

中文翻译：

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N-（吲哚-3-基）哌啶-4-羧酸作为自身免疫性疾病的RORγt变构抑制剂的发现。

抗IL-17单克隆抗体（即Cosentyx和Taltz）的临床成功已验证了Th17途径调节剂可用于治疗自身免疫性疾病。核激素受体RORγt是Th17细胞的主要调节因子，影响包括IL-17A，IL-17F，IL-22，IL-26和GM-CSF在内的多种细胞因子的产生。在学术界和工业界都引起了广泛的兴趣，以寻求适合于抑制RORγt的小分子。过去几年中已报道了多种RORγt抑制剂，其中大多数是正构结合剂。在这里，我们公开了发现和优化一类抑制剂的方法，这些抑制剂与别构结合袋的结合方式不同。从活性较弱的打击1开始，快速鉴定出了具有出色效价，选择性，和脱靶配置文件。进一步的优化集中在改善代谢稳定性上。用哌啶基羧酸盐取代苯甲酸部分，将14中的4-氮杂-吲唑核心修饰为4-F-吲唑，并引入关键的羟基基团导致25的发现，它具有出色的效能和选择性，以及适合口服给药的改善的药代动力学特征。