School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, PR China.
School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, PR China.
Eur J Med Chem. 2021 Mar 5;213:113174. doi: 10.1016/j.ejmech.2021.113174. Epub 2021 Jan 20.
In order to discover and develop drug-like anti-inflammatory agents against arthritis, based on "Hit" we found earlier and to overcome drawbacks of toxicity, twelve series of total 89 novel pyrimidine, pyrazolo[4,3-d]pyrimidine and thieno[3,2-d]pyrimidine derivatives were designed, synthesized and screened for their anti-inflammatory activity against NO and toxicity for normal liver cells (LO2). Relationships of balance toxicity and activity have been summarized through multi-steps, and title compounds 22o, 22l were found to show lower toxicity (against LO2: IC = 2934, 2301 μM, respectively) and potent effect against NO release (IR = 98.3, 97.67%, at 10 μM, respectively). Furthermore, compound 22o showed potent iNOS inhibitory activity with value of IC is 0.96 μM and could interfere stability and formation of the active dimeric iNOS. It's anti-inflammatory activity in vivo was assessed by AIA rat model. Furthermore, the results of metabolic stability, CYP, PK study in vivo, acute toxicity study and subacute toxicity assessment indicated this compound had good drug-like properties for treatment.
为了发现和开发针对关节炎的类药性抗炎药物，我们基于早期发现的“命中”化合物，设计并合成了 12 个系列共 89 种新型嘧啶、吡唑并[4,3-d]嘧啶和噻吩并[3,2-d]嘧啶衍生物，以评估它们对 NO 的抗炎活性和对正常肝细胞（LO2）的毒性。通过多步总结了平衡毒性和活性的关系，发现标题化合物 22o 和 22l 具有较低的毒性（对 LO2：IC=2934、2301μM，分别）和对 NO 释放的强大抑制作用（IR=98.3、97.67%，在 10μM 时，分别）。此外，化合物 22o 对 iNOS 的抑制活性较强，IC 值为 0.96μM，可干扰活性二聚体 iNOS 的稳定性和形成。该化合物在佐剂性关节炎大鼠模型中的抗炎活性也进行了评估。此外，代谢稳定性、CYP、体内 PK 研究、急性毒性研究和亚急性毒性评估的结果表明，该化合物具有良好的类药性，可用于治疗。
