Zeng Fanxun, Li Shiliang, Yang Guantian, Luo Yating, Qi Tiantian, Liang Yingfan, Yang Tingyuan, Zhang Letian, Wang Rui, Zhu Lili, Li Honglin, Xu Xiaoyong
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.
Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.
Acta Pharm Sin B. 2020 Oct 15;11(3):795-809. doi: 10.1016/j.apsb.2020.10.008.
Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog was identified as the lead compound for structure-activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds and ‒ with IC values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound also displayed favorable pharmacokinetic (PK) profiles and encouraging anti-arthritic effects in a dose-dependent manner.
人二氢乳清酸脱氢酶（DHODH）是开发治疗癌症和免疫疾病（如类风湿性关节炎（RA）、银屑病和多发性硬化症（MS））疗法的一个可行靶点。在此，设计并合成了一系列基于丙烯酰胺的新型DHODH抑制剂作为潜在的RA治疗药物。2-丙烯酰胺基苯甲酸类似物被确定为用于构效关系（SAR）研究的先导化合物。用萘基部分取代苯基可将抑制活性显著提高到两位数纳摩尔范围。进一步的结构优化表明，在2-位带有小的疏水基团（甲基、氯或溴）的丙烯酰胺是优选的。此外，在苯甲酸的5-位添加一个氟原子可增强效力。优化工作得到了强效化合物 和 ，其IC值分别为41、44、32和42 nmol/L。最有效的化合物 还表现出良好的药代动力学（PK）特征，并以剂量依赖的方式产生令人鼓舞的抗关节炎作用。
