背景：γ分泌酶（GS）是一种复杂的多亚基复合物，它可以切割各种跨膜蛋白。现在它是许多疾病的治疗目标。然而,由于一些副作用,GSI的临床开发并不成功。因此,寻找有效的GSI已成为药物发现的关键点。涵盖的领域：这篇综述讨论了GS和各种类型的GSI的结构和功能。本文旨在概述2013年至2015年发布的专利或申请，其中声称新型化学类别可以抑制GS。专家意见：首先，进一步了解GS的结构和功能以阐明疾病机制和开发AD治疗方法迫在眉睫。其次,如果生物等效性，药代动力学和选择性可以大大提高，一些失败的临床抑制剂仍然可以成为有希望的临床试验化合物。第三，在GSI的发展过程中暴露了一些弱点，尤其是效力不足，脑穿透力低，选择性差。最后,寻找有效和选择性的GSI是未来的主要方向。此外，在GSI试验中寻找新的适应症和给药方案也可以被视为新的方法。
BACKGROUND: Gamma secretase (GS) is an intricate and multi-subunits complex, and it can cut various transmembrane proteins. Now it is a therapeutic target for a number of diseases. However, due to some side effects, the clinical development of GSI is not successful. Therefore, searching for effective GSIs has become a key point in drug discovery. Areas covered: This
review discusses the structure and function of GS and various types of GSIs. And this article seeks to give an overview of the patents or applications published from 2013 to 2015 in which novel chemical classes are claimed to inhibit the GS. Expert opinion: Firstly, further understanding the structure and function of GS to elucidate the disease mechanism and develop AD therapies is urgent. Secondly, if the bioequivalence, pharmacokinetics and selectivity can be improved greatly, some failed clinical inhibitors still can become the promising compounds for clinical trials. Thirdly, some weaknesses are exposed during the development of GSI, especially the insufficient potency, low brain penetration and poor selectivity. Finally, to find potent and selective GSI is the major direction in future. Moreover, to find new indications and dosing regimens in a trial of GSIs also can be seen as new ways.
