The nuclear receptor retinoic acid receptor-related orphan receptor γ (RORγ, NR1F3, or RORc) exists in two isoforms, with one isoform (RORγ or RORc1) widely expressed in a variety of tissues, and the expression of the second isoform (RORγt or RORc2) restricted to the thymus and cells of the immune system. RORγt is a key regulator of the development and functions of T-helper 17 (Th17) cells. Clinical proof-of-concept (PoC) with small molecule inverse agonists of RORγt has been achieved with VTP-43742 (Phase II) for the treatment of psoriasis, and pre-clinical PoC for this mechanism has also been established for the treatment of autoimmune diseases. A series of aryl sulfonyl derivatives as novel RORγt inverse agonists were designed and synthesized based on VTP-43742. We conducted structural modifications that improved the activity profile. In pharmacodynamic (PD) studies, oral administration of compound b12 showed robust and dose-dependent inhibition of IL-6 and IL-17A cytokine expression. The ability of compound b12 to reduce the levels of IL-6 and IL-17A in vivo after oral dosing in mice, and a corresponding reduction in skin inflammation further supports the potential of small molecule RORγt modulation as a therapeutic target for the treatment of inflammatory diseases.

核受体视黄酸受体相关的孤儿受体 γ（RORγ、NR1F3 或 RORc）以两种亚型存在，其中一种亚型（RORγ 或 RORc1）在多种组织中广泛表达，第二种亚型（RORγt 或RORc2) 仅限于胸腺和免疫系统细胞。RORγt 是T发育和功能的关键调节因子-辅助 17 (Th17) 细胞。VTP-43742 (Phase II) 已实现 RORγt 小分子反向激动剂的临床概念验证 (PoC) 用于治疗银屑病，并且该机制的临床前 PoC 也已建立用于治疗自身免疫性疾病。基于VTP-43742设计合成了一系列芳基磺酰基衍生物作为新型RORγt反向激动剂。我们进行了结构修改，改善了活动概况。在药效学 (PD) 研究中，化合物b12的口服给药显示出对 IL-6 和 IL-17A 细胞因子表达的强烈和剂量依赖性抑制。化合物b12降低体内IL-6 和 IL-17A 水平的能力在小鼠口服给药后，皮肤炎症的相应减少进一步支持了小分子 RORγt 调节作为治疗炎症性疾病的治疗靶点的潜力。