Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China; Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, PR China.
Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
Bioorg Chem. 2019 May;86:44-51. doi: 10.1016/j.bioorg.2019.01.011. Epub 2019 Jan 7.
Human dihydroorotate dehydrogenase (hDHODH) is a flavin-dependent enzyme essential to pyrimidine de novo biosynthesis, which serves as an attractive therapeutic target for the treatment of autoimmune disorders. A novel series of hDHODH inhibitors was developed based on a lead which was obtained by a medicinal chemistry exploration. Most compounds showed moderate to significant potency against hDHODH, compounds 5d, 5e, and 6a effectively inhibited the activities of hDHODH with IC values from 0.9 to 2.8 μM. Further studies showed that compound 5e also effectively suppressed proliferation of the activated PBMCs (IC = 20.35 μM). Surprisingly, compound 5e also showed anti-pulmonary fibrotic activity similar to that of pirfenidone in vitro assay. Therefore, compound 5e might have potential to be developed as a novel hDHODH inhibitors for autoimmune diseases therapy.
人源二氢乳清酸脱氢酶（hDHODH）是嘧啶从头合成所必需的黄素依赖酶，是治疗自身免疫性疾病的有吸引力的治疗靶点。基于通过药物化学探索获得的先导化合物，开发了一系列新型 hDHODH 抑制剂。大多数化合物对 hDHODH 表现出中等至显著的抑制活性，化合物 5d、5e 和 6a 有效地抑制 hDHODH 的活性，IC 值为 0.9 至 2.8 μM。进一步的研究表明，化合物 5e 还能有效抑制活化的 PBMCs 的增殖（IC = 20.35 μM）。令人惊讶的是，化合物 5e 在体外试验中也表现出与吡非尼酮相似的抗肺纤维化活性。因此，化合物 5e 可能具有作为新型 hDHODH 抑制剂用于治疗自身免疫性疾病的潜力。
