Structural optimization and biological evaluation of 1,5-disubstituted pyrazole-3-carboxamines as potent inhibitors of human 5-lipoxygenase

Acta Pharmaceutica Sinica B

Jihui Zhao¹  Yu Zhou¹  Mingyue Zheng¹  Hong Liu¹  Chunyi Jiang¹  Deju Ye¹  Mingfang Zheng¹  Dongxiang Liu¹  Dong Zhang¹  Hualiang Jiang¹  Jun Liu²  Jian Cheng³  Xiaomei Zhou³  Shuli Zheng³ 

[1] CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;China Pharmaceutical University, Nanjing 210009, China;Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou 215006, China;

关键词: 5-Lipoxygenase;    5-LOX inhibitors;    Pyrazole derivatives;    Leukotrienes-related diseases;    In vivo;    Benzo-fused heterocycle;    Ischemic incults;    Brain inflammation;   

DOI  :  10.1016/j.apsb.2015.11.004

来源: DOAJ

【 摘 要 】

Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1 µmol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused-ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders.

【 授权许可】

Unknown