title: Syntheses and in-vitro evaluation of novel adamantane based γ-secretase inhibitors.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, PA, 19104, USA.
authors.forename: A O
authors.initials: AO
authors.lastname: Adeniji
authors.forename: R M
authors.initials: RM
authors.lastname: Wells
authors.forename: A
authors.initials: A
authors.lastname: Adejare
mesh_terms: D000218:Adamantane / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular
chemical_list: D053829:Amyloid Precursor Protein Secretases; D000218:Adamantane