Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor γ-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease
Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor γ-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease
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发现口服视黄酸受体相关孤儿受体γ-t/二氢乳清酸脱氢酶双重抑制剂用于治疗难治性炎症性肠病
DOI：
10.1021/acs.jmedchem.1c01746
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发表时间：
2021-12-27
影响因子：
7.3
通讯作者：
Wang, Yonghui
中科院分区：
文献类型：
--
作者：
Chen, Ji-An;Ma, Hui;Wang, Yonghui
炎症性肠病（IBD）是一种多因素的自身免疫性疾病，代表了一个主要的临床挑战。本文提出了一种采用维甲酸受体相关孤儿受体γ-t（ROR γ t）和二氢乳清酸脱氢酶（DHODH）的双靶向方法治疗IBD的策略。预期双重ROR γ t/DHODH抑制剂不仅减少ROR γ t驱动的Th 17细胞分化，而且减轻T细胞的扩增和活化，这可能增强抗炎作用。从2-氨基苯并噻唑开始，发现了一系列2-氨基四氢苯并噻唑作为有效的双重ROR γ t/DHODH抑制剂。化合物14 d对ROR γ t的IC 50值为0.110 μ M，对DHODH的IC 50值为0.297 μ M。在小鼠药代动力学特征可接受的情况下，14 d表现出显著的体内抗炎活性，并且剂量依赖性地减轻葡聚糖硫酸钠（DSS）诱导的小鼠急性结肠炎的严重程度。总之，本研究为开发治疗IBD的治疗剂提供了一个新的框架。
Inflammatory bowel disease (IBD) is a multifactorial autoimmune disease, representing a major clinical challenge. Herein, a strategy of dual-targeting approach employing retinoic acid receptor-related orphan receptor gamma-t (ROR gamma t) and dihydroorotate dehydrogenase (DHODH) was proposed for the treatment of IBD. Dual ROR gamma t/DHODH inhibitors are expected not only to reduce ROR gamma t-driven Th17 cell differentiation but also to mitigate the expansion and activation of T cells, which may enhance anti-inflammatory effects. Starting from 2-aminobenzothiazole hit 1, a series of 2-aminotetrahydrobenzothiazoles were discovered as potent dual ROR gamma t/DHODH inhibitors. Compound 14d stands out with IC50 values of 0.110 mu M for ROR gamma t and of 0.297 mu M for DHODH. With acceptable mouse pharmacokinetic profiles, 14d exhibited remarkable in vivo anti-inflammatory activity and dose-dependently alleviated the severity of dextran sulfate sodium (DSS)-induced acute colitis in mice. Taken together, the present study provides a novel framework for the development of therapeutic agents for the treatment of IBD.