Syntheses and In-Vitro Evaluation of Novel Adamantane Based γ-Secretase Inhibitors

Author(s): A. O. Adeniji, R. M. Wells, A. Adejare.

Journal Name: Current Medicinal Chemistry

Volume 19 , Issue 15 , 2012

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Abnormal processing of amyloid precursor protein (APP) by β - and γ -secretases to produce excess amyloid-β-peptide is believed to contribute to the pathophysiological cascade that results in Alzheimer’s disease. γ -Secretase inhibition or modulation therefore represents a rational approach to the prevention and/or management of AD. Here, we present the discovery and SAR of a class of novel adamantanyl sulfonamide based γ -secretase inhibitors. Activity evaluation was conducted on cell lines overexpressing APP (wild type and Swedish mutation). Our results suggest size threshold and hydrogen bond formation are necessary for inhibitory activity. There was no correlation between compound activity, Log P, and the electronic effect of substituents on the aromatic ring. These compounds possess desirable drug like properties and results of the study can guide a pharmacophore based design of γ -secretase inhibitors.

Keywords: Alzheimer’s disease (AD), α-secretase, amyloid-β-peptide (Aβ), amyloid precursor protein (APP), APP swedish mutation (APPswe), aspartyl protease, β-secretase, intramembrane proteolytic cleavage, plaques, neurofibrillary tangles, sulfonamides, γ -secretase inhibitors, inhibitors.

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Article Details

Year: 2012
Page: [2458 - 2471]
Pages: 14
DOI: 10.2174/092986712800269353
Price: $58

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