4-(2-((1r)-1-(((4-chlorophenyl)sulfonyl)-2-5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic-acid and Alzheimer-Disease

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

N-Sulfonylated and N-alkylated carbazolyloxyacetic acids were investigated for the inhibition and modulation of the Alzheimer's disease associated gamma-secretase. The introduction of a lipophilic substituent, which may vary from arylsulfone to alkyl, turned 2-carbazolyloxyacetic acids into potent gamma-secretase modulators. This resulted in the selective reduction of Abeta(42) and an increase of the less aggregatory Abeta(38) fragment by several compounds (e.g., 7d and 8c). Introduction of an electron donating group at position 6 and 8 of N-substituted carbazolyloxyacetic acids either decreased the activity or inversed modulation. The most active compounds displayed activity on amyloid precursor protein (APP) overexpressing cell lines in the low micromolar range and little or no effect on the gamma-secretase cleavage at the epsilon-site.

Topics: Acetates; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Humans

The enzyme gamma-secretase has long been considered a potential pharmaceutical target for Alzheimer disease. Presenilin (the catalytic subunit of gamma-secretase) and signal peptide peptidase (SPP) are related transmembrane aspartyl proteases that cleave transmembrane substrates. SPP and gamma-secretase are pharmacologically similar in that they are targeted by many of the same small molecules, including transition state analogs, non-transition state inhibitors, and amyloid beta-peptide modulators. One difference between presenilin and SPP is that the proteolytic activity of presenilin functions only within a multisubunit complex, whereas SPP requires no additional protein cofactors for activity. In this study, gamma-secretase inhibitor radioligands were used to evaluate SPP and gamma-secretase inhibitor binding pharmacology. We found that the SPP enzyme exhibited distinct binding sites for transition state analogs, non-transition state inhibitors, and the nonsteroidal anti-inflammatory drug sulindac sulfide, analogous to those reported previously for gamma-secretase. In the course of this study, cultured cells were found to contain an abundance of SPP binding activity, most likely contributed by several of the SPP family proteins. The number of SPP binding sites was in excess of gamma-secretase binding sites, making it essential to use selective radioligands for evaluation of gamma-secretase binding under these conditions. This study provides further support for the idea that SPP is a useful model of inhibitory mechanisms and structure in the SPP/presenilin protein family.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Anti-Inflammatory Agents, Non-Steroidal; Aspartic Acid Endopeptidases; Binding Sites; Catalytic Domain; Cell Line; Humans; Ligands; Models, Molecular; Presenilins; Protease Inhibitors; Sulindac