Abstract：
Pimavanserin is a selective 5-HT2A receptor antagonist and inverse agonist approved by the FDA in 2016, which is used to treat patients with Parkinson\'s disease psychosis (PDP). But pimavanserin has potential risk with increasing mortality in elderly patients and also increasing the risk of QT interval prolongation in patients. Therefore, searching for new drugs with high efficacy and low toxicity is urgently needed. Based on the docking study of pimavanserin, a series of novel pimavanserin derivatives (7-1∼7-37) were designed and synthesized. The biological activities were evaluated by cell assays and compound 7-16 exhibited 50-fold higher 5-HT2A receptor antagonist activity (IC50 = 0.54 vs 27.3 nM) and 23-fold higher inverse agonist activity (IC50 = 2.1 vs 50 nM) than pimavanserin. Moreover, 7-16 showed increased potency window between the 5-HT2A and hERG activities than pimavanserin. Furthermore, compound 7-16 demonstrated excellent in vitro and in vivo pharmacokinetics, 4-fold more improvement in functional activity in vivo, and good safety profile. Therefore, compound 7-16 represents a potentially promising candidate as a novel anti-PDP agent that warrants further investigation.
摘要：
Pimavanserin是FDA于2016年批准的选择性5-HT2A受体拮抗剂和反向激动剂，用于治疗帕金森病精神病（PDP）患者。但是吡马色林具有潜在的风险，增加老年患者的死亡率，并增加患者QT间期延长的风险。因此,迫切需要寻找高效低毒的新药。基于匹马色林的对接研究,设计并合成了一系列新型匹马色林衍生物（7-1~7-37）。通过细胞测定评估生物活性,并且化合物7-16表现出比匹马色林高50倍的5-HT2A受体拮抗剂活性(IC50=0.54对27.3nM)和高23倍的反向激动剂活性(IC50=2.1对50nM)。此外，图7-16显示5-HT2A和hERG活性之间的效力窗口比匹马色林增加。此外，化合物7-16表现出优异的体外和体内药代动力学，体内功能活性提高4倍，和良好的安全性。因此,化合物7-16代表了作为新型抗PDP剂的潜在有希望的候选物,值得进一步研究。
