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Synthesis and Biological Evaluation of 3-Amino-4-aryl-piperidine Derivatives as BACE 1 Inhibitors
| Content Provider | Semantic Scholar |
|---|---|
| Author | Lim, Hee-Jong Jung, M. H. Lee, Ihl Young Choi Park, Woo Kyu |
| Copyright Year | 2006 |
| Abstract | Alzheimer’s disease (AD) is a progressive neurodegenerative disease and most common form of dementia affecting about 20 millions worldwide, which has clinical symptoms of memory loss, impairment of daily living activity, and ultimately leads to death. AD is characterized pathologically by deposition of senile plaques and neurofibrillary tangles found in the brain of post-mortem AD patients. Amyloid β peptide (Aβ), a major component of senile plaques, is derived from amyloid precursor protein (APP) by sequential endoproteolysis by βand γ-secretase. Numerous evidences suggest that an excessive level of Aβ as soluble oligomers and filamentous fibrils initiate neuronal loss and play a causative role in the disease process. Consequently, inhibition of Aβ formation would prevent and suppress the development of AD. BACE 1 (β-secretase), a membrane bound aspartic protease, is a key enzyme responsible for APP processing into Aβ peptide and thus considered a promising therapeutic target for the treatment of AD. Although numerous peptidomimetic BACE 1 inhibitors, derived from statine, hydroxyethylene, hydroxyethylamine, hydroxymethylcarbonyl, and aminoethylamine as a transition state mimic core motif frequently found in other aspartic protease inhibitors, are highly active in enzymatic assay, they would not be potential drug leads due to their poor cell permeability and bioavailability. Recently, endeavors to develop nonpeptide cell permeable BACE 1 inhibitors have been extensively studied, and various scaffolds such as isophthalamide, diphenylurea, piperazine, and piperidine were reported to possess BACE 1 inhibitory activity. 4-Aryl-3-alkoxypiperidines have been reported to bind to carboxyl group of aspartic residue in the active site of human renin in a similar binding mode to the binding of peptidomimetic inhibitors derived from statin and aminostatin and shown very potent activity against renin, but they have not been fully studied in the development of BACE 1 inhibitors. We anticipated new highly active nonpeptidomimetic BACE 1 inhibitors could be developed by modification of piperidine scaffold with appropriate substituents. In this study, we present the synthesis and BACE 1 inhibitory activity of optically pure (3R)-amino-(4R)-arylpiperidine derivatives. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://ocean.kisti.re.kr/downfile/volume/chemical/JCGMCS/2006/v27n9/JCGMCS_2006_v27n9_1371.pdf |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | APP protein, human Activities of Daily Living (activity) Alzheimer's Disease Amyloid beta-Protein Precursor Aspartic Acid Proteases BACE1 gene BACE1 wt Allele Bace protein, rat Carboxyl Group Dementia Diffuse Neurofibrillary Tangles with Calcification Endopeptidases Enzyme Assays Fibril - cell component Memory Disorders Motif Nerve Degeneration Neurodegenerative Disorders Patients Physical vapor deposition Senile Plaques Simvastatin Therapeutic Targets Database Tissue membrane hydroxyethylene piperazine piperidine statine |
| Content Type | Text |
| Resource Type | Article |
