γ-Secretase is an aspartyl intramembranal protease composed of presenilin, Nicastrin, Aph1, and Pen2 with 19 transmembrane domains. γ-Secretase cleaves the amyloid precursor proteins (APP) to release Aβ peptides that likely play a causative role in the pathogenesis of Alzheimer’s disease (AD). In addition, γ-secretase cleaves Notch and other type I membrane proteins. γ-Secretase inhibitors (GSIs) have been developed and used for clinical studies. However, clinical trials have shown adverse effects of GSIs that are potentially linked with nondiscriminatory inhibition of Notch signaling, overall APP processing, and other substrate cleavages. Therefore, these findings call for the development of disease-modifying agents that target γ-secretase activity to lower levels of Aβ42 production without blocking the overall processing of γ-secretase substrates. γ-Secretase modulators (GSMs) originally derived from nonsteroidal anti-inflammatory drugs (NSAIDs) display such characteristics and are the focus of this rev...

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Development and mechanism of γ-secretase modulators for Alzheimer's disease.

The Petasis boron–Mannich reaction, simply referred to as the Petasis reaction, is a powerful multicomponent coupling reaction of a boronic acid, an amine, and a carbonyl derivative. Highly functio...

Reactivity and Synthetic Applications of Multicomponent Petasis Reactions

The design and the synthesis of several chemical subclasses of imidazole containing γ-secretase modulators (GSMs) is described. Conformational restriction of pyridone 4 into bicyclic pyridone isosteres has led to compounds with high in vitro and in vivo potency. This has resulted in the identification of benzimidazole 44a as a GSM with low nanomolar potency in vitro. In mouse, rat, and dog, this compound displayed the typical γ-secretase modulatory profile by lowering Aβ42 and Aβ40 levels combined with an especially pronounced increase in Aβ38 and Aβ37 levels while leaving the total levels of amyloid peptides unchanged.

Design and synthesis of a novel series of bicyclic heterocycles as potent γ-secretase modulators.

Introduction: γ-Secretase is the enzyme responsible for the final step of amyloid precursor protein proteolysis to generate Aβ peptides including Aβ42 which is believed to be a toxic species involved in Alzheimer's disease (AD) progression. γ-Secretase modulators (GSMs) have been shown to selectively lower Aβ42 production without affecting total Aβ levels or the formation of γ-secretase substrate intracellular domains such as APP intracellular domain and Notch intracellular domain. Therefore, GSMs have emerged as an important therapeutic strategy for the treatment of AD. Areas covered: The literature covering novel GSMs will be reviewed focusing on patents from 2010 to 2012. Expert opinion: During the last review period (2008 – 2010) considerable progress was made developing GSMs with improved potency for lowering Aβ42 levels, but most of the compounds resided in unfavorable central nervous system (CNS) drug space. In this review period (2010 – 2012), there is a higher percentage of potent GSM chemical ma...

Novel γ-secretase modulators for the treatment of Alzheimer's disease: a review focusing on patents from 2010 to 2012.

This chapter reviews the current status of γ-secretase modulators, highlighting key compounds by each company involved in the area The review focuses on the three main chemotypes: acids, imidazoles and related derivatives and natural products A section on chemical biology and ligand-binding site elucidation studies is also included The primary source of information is drawn from peer reviewed literature as this permits analysis of PK–PD relationships and subsequent comment Discussion of the patent literature is included for completeness From this analysis, the key issues and challenges in the area are highlighted The review concludes with a summary of the clinical development status and comment on future prospects of the field

γ-Secretase Modulators: Current Status and Future Directions

We have investigated a novel series of acid-derived γ-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which lowered Aβ42, increased Aβ38, but had little to no effect on Aβ40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain Aβ42 levels in CF-1 mice and Fischer rats, as well as plasma Aβ42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.

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Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator.

Background: In recent years, there has been a growing interest in automating small-molecule bioanalytical sample preparations specifically using the Hamilton MicroLab® STAR liquid-handling platform. In the most extensive work reported thus far, multiple small-molecule sample preparation assay types (protein precipitation extraction, SPE and liquid–liquid extraction) have been integrated into a suite that is composed of graphical user interfaces and Hamilton scripts. Using that suite, bioanalytical scientists have been able to automate various sample preparation methods to a great extent. However, there are still areas that could benefit from further automation, specifically, the full integration of analytical standard and QC sample preparation with study sample extraction in one continuous run, real-time 2D barcode scanning on the Hamilton deck and direct Laboratory Information Management System database connectivity. Results: We developed a new small-molecule sample-preparation automation system that imp...

Lawrence Gan

Papers

Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator.

MARS: bringing the automation of small-molecule bioanalytical sample preparations to a new frontier