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 11 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 42 and 53‒55 with IC₅₀ values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo 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（例如类风湿关节炎 (RA)、牛皮癣和多发性硬化症 (MS)）的疗法的可行靶点。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 治疗剂。2-丙烯酰胺基苯甲酸类似物11被确定为构效关系 (SAR) 研究的先导化合物。用萘基部分取代苯基将抑制活性显着提高至两位数纳摩尔范围。进一步的结构优化表明，在2位具有小的疏水基团（Me、Cl或Br）的丙烯酰胺是优选的。此外，在苯甲酸的5位添加氟原子增强了效力。优化工作产生了有效的化合物42 和 53-55 ， IC 50值分别_为41、44、32 和 42 nmol/L。最有效的化合物54还表现出良好的药代动力学 (PK) 特征，并以剂量​​依赖性方式促进体内抗关节炎作用。