γ-Secretase inhibitors and modulators.

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

A Pd(II)-catalyzed enantioselective C–H cross-coupling of benzylamines via kinetic resolution has been achieved using chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) ligands. Both chiral benzylamines and ortho-arylated benzylamines are obtained in high enantiomeric purity. The use of a readily removable nosyl (Ns) protected amino group as the directing group is a crucial practical advantage. Moreover, the ortho-arylated benzylamine products could be further transformed into chiral 6-substituted 5,6-dihydrophenanthridines as important structural motifs in natural products and bioactive molecules.

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Kinetic Resolution of Benzylamines via Palladium(II)-Catalyzed C–H Cross-Coupling

Recent therapeutic strategies targeting beta amyloid and tauopathies in Alzheimer's disease.

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.

http://jpkc.fudan.edu.cn/picture/article/84/7e298344-7730-40bc-af5c-08d97cd1bbae/9f47487d-7665-4422-ae71-b5ad2605993f.pdf

Discovery of 4-aminomethylphenylacetic acids as γ-secretase modulators via a scaffold design approach.

BIIB042, a novel γ-secretase modulator, reduces amyloidogenic Aβ isoforms in primates and rodents and plaque pathology in a mouse model of Alzheimer's disease

Lin Xu

Papers

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

Discovery of 4-aminomethylphenylacetic acids as γ-secretase modulators via a scaffold design approach.

BIIB042, a novel γ-secretase modulator, reduces amyloidogenic Aβ isoforms in primates and rodents and plaque pathology in a mouse model of Alzheimer's disease