Fenchylamine Sulfonamide Inhibitors of Amyloid β Peptide Production by the γ-Secretase Proteolytic Pathway:  Potential Small-Molecule Therapeutic Agents for the Treatment of Alzheimer's Disease

• Published in: Journal of medicinal chemistry 2000-06, Vol.43 (12), p.2297-2299
• Main Authors: Rishton, Gilbert M, Retz, Daniel M, Tempest, Paul A, Novotny, James, Kahn, Steve, Treanor, James J. S, Lile, Jack D, Citron, Martin
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - biosynthesis; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Biological and medical sciences; Cell Line; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Endopeptidases - metabolism; Humans; Medical sciences; Miscellaneous; Neurology; Neuropharmacology; Norbornanes - chemical synthesis; Norbornanes - chemistry; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990622z

The brain plaques associated with Alzheimer's disease (AD) are composed primarily of the amyloid beta peptides (A beta 40,42) which are produced from the proteolytic processing of the beta -amyloid precursor protein (APP). The production of A beta from APP proceeds via two cleavages which are catalyzed by distinct protease activities known as the secretases. The cleavage of APP at the A beta N-terminal residue is catalyzed by the recently cloned and characterized aspartic acid protease named beta -secretase. The A beta C-terminal cleavage which occurs at the transmembrane region of APP is attributed to the action of the yet unknown protease(s) designated gamma -secretase(s). In the brain of the AD patient, aggregates of A beta peptides are deposited resulting in formation of the insoluble plaques and vascular deposits characteristic of AD pathology. The overproduction of the relatively hydrophobic A beta 42 component has been particularly associated with plaque formation. Genetic evidence suggests elevated brain levels of A beta 42 to be the cause of early-onset familial AD. Inhibition of the beta - and gamma -secretase proteolytic pathways would be expected to decrease the production of A beta and potentially to slow the progression of AD. Cellular assays to measure inhibition of the overproduction of A beta 42 have recently been developed. These assays have allowed the initiation of investigations toward the discovery of small-molecule inhibitors of A beta production in cell culture. Among the reports of A beta production inhibitors in the patent literature, the cyclohexylalanine-based statine 1 and the lipophilic dimethylaminoethyl tetralin 2 serve as examples of chemically stable small-molecule inhibitors of A beta production in cell culture.