Structure activity relationship (SAR) studies of a novel gamma-secretase inhibitor

Abnormal processing of amyloid precursor protein 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 (AD). Current therapy however involves the use of anticholinesterases and more recently an NMDA receptor antagonist, therapeutic agents that do not address the underlying pathology of AD. γ-Secretase inhibition thus represents a rational, etiology based approach to the prevention and/or management of AD. Results of structure activity relationship studies (SAR) and in-vitro evaluation of a class of novel sulfonamide γ-secretase inhibitors are presented. These compounds possess desirable drug like properties and exhibited inhibitory activity when tested on two cell lines overexpressing APP (wild type and swedish mutation). Replacement of the acidic sulfonamide hydrogen with alkyl groups led to loss or reduction of activity. There was no correlation between activity of the compounds, Log P, and the electronic density on the aromatic ring. Our results however suggest a size requirement. Results of this study can serve as guide for a pharmacophore based design of γ-secretase inhibitors.