物理化学与生物实验协同开发环氧化酶-2 抑制剂。

Synergy of Physico-chemical and Biological Experiments for Developing a Cyclooxygenase-2 Inhibitor.

机构信息

Department of Chemistry, Centre for Advanced Studies, Guru Nanak Dev University, Amritsar, 143005, India.

Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India.

出版信息

Sci Rep. 2018 Jul 3;8(1):10005. doi: 10.1038/s41598-018-28408-8.

The physiological consequences of COX-2 overexpression in the development of cancer, diabetes and neurodegenerative diseases have made this enzyme a promising therapeutic target. Herein, COX-2 active site was analyzed and new molecules were designed. We identified a highly potent molecule (S)-3a with IC value and the selectivity for COX-2 0.6 nM and 1666, respectively. The MTD of (S)-3a was 2000 mg kg and its pharmacokinetic studies in rat showed t 7.5 h. This compound reversed acetic acid induced analgesia and carragennan induced inflammation by 50% and 25% in rat when used at a dose 10 mg kg. Mechanistically, it was found that compound (S)-3a inhibits COX-2. Overall, the combination of physico-chemical and biological experiments facilitated the development of a new lead molecule to anti-inflammatory drug.

COX-2 过表达在癌症、糖尿病和神经退行性疾病发展中的生理后果使这种酶成为有前途的治疗靶点。在此，对 COX-2 的活性部位进行了分析，并设计了新的分子。我们鉴定出一种高活性分子 (S)-3a，其 IC 值和对 COX-2 的选择性分别为 0.6 nM 和 1666。(S)-3a 的最大耐受剂量为 2000 mg/kg，其在大鼠中的药代动力学研究表明 t 为 7.5 h。当以 10 mg/kg 的剂量使用时，该化合物可使大鼠的醋酸诱导镇痛和角叉菜胶诱导炎症分别逆转 50%和 25%。从机制上讲，发现化合物 (S)-3a 抑制 COX-2。总的来说，物理化学和生物实验的结合促进了一种新的抗炎药物先导分子的发展。