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

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 mu mol/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. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

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 IC_(50) values less than 1 mmol/L in cell-based assays.Here,we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fusedring 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 andin 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.