ly-450139 and Alzheimer-Disease

The γ-secretase is a large transmembrane protein complex composed of four distinct units. It has aroused numerous attention over the past two decades as its intriguing role in mediating intramembrane proteolysis. γ-Secretase controls the cleavage of a broad ranged substrates, part of which have implicated in the pathogenesis of Alzheimer's disease, inflammation, and tumorigenesis. The disclosure of the atomic structure of the γ-secretase complex through cryo-EM in recent years has facilitated the understanding of its physiological roles, as well as enabled rational design of novel γ-secretase targeting molecules. This review highlights the recent progress of γ-secretase inhibitors and modulators under either clinical or preclinical stages, as well as their potential uses against various biological indications.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Cell Membrane; Humans

Alzheimer's disease (AD) is a neurodegenerative disease, characterized by progressive loss of memory which is associated with other cognitive deficits. The two protein structures in the brain i.e. neurofibrillary tangles and senile plaques are considered to hamper the normal cognitive activity of the brain. There are various therapeutic interpolations under investigation to thwart and treat AD. Secretases inhibitors are important agents that inhibit the development of senile plaques. β-secretase (BACE) inhibitors are in lime light for the drug development of AD. BACE initiates the production of Aβ, so its inhibition provides a valid target for the AD. BACE inhibitors viz. LY2811376, LY2886721, E2609 are in different phases of clinical trials. However, chemical study of MK8931 was discontinued due to lack of chances of finding a positive clinical effect.. The review incorporates exhaustive literature reports on secretase inhibitors, γ-secretase modulators (GSMs) and α-secretase enhancers. The recent studies on the natural products as GSMs have also been included.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Enzyme Inhibitors; Humans; Plaque, Amyloid

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Drug Discovery; Humans; Models, Biological; Protease Inhibitors

gamma-Secretase inhibitors have been shown to reduce the production of beta-amyloid, a component of the plaques that are found in brains of patients with Alzheimer's disease. A novel series of heterocyclic sulfonamide gamma-secretase inhibitors that reduce beta-amyloid levels in cells is reported. Several examples of compounds within this series demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative gamma-secretase substrate.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; CHO Cells; Cricetinae; Cricetulus; Heterocyclic Compounds; Humans; Molecular Structure; Protein Binding; Receptors, Notch; Structure-Activity Relationship; Sulfonamides

Using a cell-based assay, we have identified a new series of Notch-sparing gamma-secretase inhibitors from HTS screening leads 2a and 2e. Lead optimization studies led to the discovery of analog 8e with improved gamma-secretase inhibitory potency and Notch-sparing selectivity.

Topics: Alzheimer Disease; Amyloid; Amyloid Precursor Protein Secretases; Carbon; Chemistry, Pharmaceutical; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Models, Chemical; Receptors, Notch; Structure-Activity Relationship

SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors; Mice; Mice, Transgenic; Models, Molecular; Molecular Conformation; Receptor, Notch1; Stereoisomerism; Structure-Activity Relationship; Sulfonamides; Thiophenes