Gamma secretase inhibitors: a patent review (2013 - 2015)

ABSTRACT

Introduction: 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.

KEYWORDS:

• Alzheimer’s disease
• amyloid β protein
• amyloid precursor protein
• gamma secretase
• gamma secretase inhibitor
• Notch
• cancer

Article highlights

• GS is the catalytic core of a multi-subunits intramembrane cleaving protease which plays an important role in the production of amyloid β (Aβ) by regulating the proteolytic processing of APP.

• Presenilin (PS) heterodimer, Nicastrin (NCT), Anterior pharynx-defective 1 (APH-1) and Presenilin enhancer-2 (PEN-2) are vital assemblies for the activity of GS, although the structure of human GS has been reported, there is an urgent to better understand the relationships of the structure and function of GS in order to elucidate the disease mechanism and develop effective AD therapies.

• GSI is also applied in the intramembrane proteolysis of Notch to block the normal signaling, and it leads to the non-selectivity of GSI, which could be seen as the most serious barrier for the discovery of selective GSI.

• A large number of GSIs from peptide to non-peptide are disclosed, providing various lead compounds for designing and optimizing for targeting GS, but most GSIs are troubled with some problems, no sufficient potency, low brain penetration and poor selectivity.

• Although all clinical trials for treating AD with GSIs have failed to date，GSIs also can become the promising compounds in clinical trials for AD if the bioequivalence, pharmacokinetic and selectivity can be improved.

• In terms of the patents, new indications and dosing regimens in a trial recently attract the attentions of researchers with the aim to expand the range of clinical application and improve the results of clinical trials.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper received funding from National Natural Science Foundation of China (81402851 and 81573281) and Fundamental Research Funds for the Central Universities (2015ZD009).