Shao Liming, Li Wei, Xie Qiong, Yin Hong
Fudan University, School of Pharmacy, Department of Medicinal Chemistry , 826 Zhangheng Road, Pudong Xinqu, Shanghai, 201203 , P.R. China +86 21 51980126 ;
Expert Opin Ther Pat. 2014 Feb;24(2):131-54. doi: 10.1517/13543776.2014.859676. Epub 2013 Nov 30.
The dysfunctions of three very important monoamine neurotransmitters, serotonin (5-HT), norepinephrine (NE) and dopamine (DA), are associated with some of important CNS diseases such as depression; developing the triple reuptake inhibitors (TRIs) that can rebalance 5-HT, NE and DA through the inhibition of the monoamine reuptake transporters will lead to a more effective and safer antidepressant.
This article reviews past 7 years' advances in the development of TRIs; a patent review (2006 - 2012), covering the discovery of new chemical entities, and development status of leading TRI clinical candidates.
The development of TRIs has several challenges, including discovering a "single" agent that has the activities against all three monoamine reuptake transporters SERT, NET and DAT. More important is that the agent must have a "right ratio" to be safer and better tolerated for the treatment of depression. The TRIs can potentially be used for the treatment of other CNS diseases, such as pain, Parkinson's and attention deficit hyperactivity disorder (ADHD), depending on ratios of SERT, NET and DAT.
三种非常重要的单胺类神经递质，即血清素（5-羟色胺，5-HT）、去甲肾上腺素（NE）和多巴胺（DA）功能失调与一些重要的中枢神经系统疾病相关，如抑郁症；开发能够通过抑制单胺再摄取转运体来重新平衡5-HT、NE和DA的三重再摄取抑制剂（TRIs），将产生更有效、更安全的抗抑郁药。
本文回顾了过去7年TRIs开发方面的进展；专利综述（2006 - 2012年），涵盖新化学实体的发现以及主要TRIs临床候选药物的开发状况。
TRIs的开发面临若干挑战，包括发现一种对所有三种单胺再摄取转运体（SERT、NET和DAT）均有活性的“单一”药物。更重要的是，该药物必须具有“恰当比例”，以便在治疗抑郁症时更安全且耐受性更好。根据SERT、NET和DAT的比例，TRIs可能潜在地用于治疗其他中枢神经系统疾病，如疼痛、帕金森病和注意力缺陷多动障碍（ADHD）。
