title: Gamma secretase inhibitors: a patent review (2013 - 2015).
abstract: 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.
authors.affiliation: a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.
authors.forename: Kai
authors.initials: K
authors.lastname: Gu
authors.affiliation: a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Lin
authors.affiliation: a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.affiliation: a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.
authors.forename: Jun
authors.initials: J
authors.lastname: Mo
authors.affiliation: a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.
authors.forename: Siyu
authors.initials: S
authors.lastname: He
authors.affiliation: a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.affiliation: b Key Laboratory of Biomedical Functional Materials, School of Science , China Pharmaceutical University , Nanjing , China.
authors.forename: Xueyang
authors.initials: X
authors.lastname: Jiang
authors.affiliation: a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.
authors.forename: Haopeng
authors.initials: H
authors.lastname: Sun
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D010330:Patents as Topic; D014018:Tissue Distribution
chemical_list: D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; Notch; amyloid precursor protein; amyloid β protein; cancer; gamma secretase; gamma secretase inhibitor