BRL 50481

BRL 50481是磷酸二酯酶(PDE)7的选择性抑制剂.底物浓度为50 nM和1 μM时,hrPDE7A1对cAMP的水解作用被BRL 50481抑制,IC50值分别为0.26和2.4 μM [1].BRL 50481是高效选择性人重组PDE7A抑制剂,IC50值为26 nM [2].

作为cAMP特异性的PDE,PDE7具有高亲和力.PDE7可能成为T细胞相关疾病\呼吸道疾病及中枢神经系统(CNS)疾病的有效治疗靶点[3].在1 μM和50 nM cAMP时,BRL 50481选择性抑制hrPDE7A1,抑制PDE3的效力分别低416和1884倍,抑制hrPDE4A4的效力分别低38和238倍.低于100 μM的BRL 50481并不能显著抑制PDE1C\PDE1B\PDE5 和PDE2.BRL 50481能够竞争性抑制hrPDE7A1,Ki值为180±10 nM.但在MOLT-4 T细胞中,BRL 50481提高cAMP含量,EC50值>> 100 μM.Rolipram的EC80值约为10 μM.在次最大浓度的Rolipram存在时测定10-300 μM BRL 50481对cAMP含量的影响,相比于BRL 50481和Rolipram单独处理对cAMP反应影响的总和,BRL 50481的平均浓度-反应曲线出现显著更大数量级的向上移位[1].

相比于A-350619或BRL 50481单独处理,亚甲基蓝和BRL 50481协同处理显著延迟小鼠急动和抽搐.亚甲基蓝和外源性给予BRL 50481 (2 mg/kg, i.p.)协同处理具有显著的抗惊厥活性[4].

参考文献：
[1].  Smith SJ, Cieslinski LB, Newton R, et al. Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a selective inhibitor of phosphodiesterase 7: in vitro studies in human monocytes, lung macrophages, and CD8+ T-lymphocytes. Mol Pharmacol, 2004, 66(6):1679-89.
[2].  Gil C, Campillo NE, Perez DI, et al. PDE7 inhibitors as new drugs for neurological and infl ammatory disorders. Expert Opin Ther Patents, 2008, 18(10):1127-1139.
[3].  Castro A, Jerez MJ, Gil C, et al. CODES, a novel procedure for ligand-based virtual screening: PDE7 inhibitors as an application example. Eur J Med Chem, 2008, 43(7):1349-59.
[4].  Nandhakumar J, Ernest V and Tyagi MG. Evaluation of Seizure Activity After Phospho-diesterase Inhibition (BRL 50481) with Guanylate Cyclase Activation (A-350619) and Inhibition (Methylene blue) in Animal Models of Epilepsy. J Neurol Neurophysiol, 2011, 2:110.