β-secretase inhibitors for treatment of Alzheimer's disease

Abstract

The Amyloid Precursor Protein (APP) undergoes sequential enzymatic cleavage by β-secretase (BACE1) and subsequently by γ-secretase to form the amyloid-β peptide (Aβ), the principal component of senile plaques in Alzheimer's disease (AD). BACE is a membrane bound aspartic acid protease found in the CNS. BACE is characterized by a large binding pocket designed to recognize 6-8 amino acid residues of APP. Small molecule BACE inhibitors would be expected to prevent the generation of the Aβ peptides and consequently reduce the detrimental effects of Aβ toxicity and the formation of amyloid plaques in the brain. While inhibition of BACE1 represents one of the promising therapeutic strategies for AD, development of centrally active, small molecule inhibitors have been challenging. We targeted selective inhibitors of human BACE with the appropriate balance of potency and CNS penetration using rational drug design. Inhibitor design was established from the analysis of BACE-ligand X-ray crystallographic data using a diverse array of inhibitors combined with measurement of the energetics of binding interactions. In vitro screening provided guidance on key issues of permeability and efflux due to P-glycoprotein (Pgp). This set of design features was also coupled with our contemporary understanding of the desirable physical property profile of CNS drugs. A strategy to align a set of physicochemical properties into a single molecule led to the discovery of a novel class of BACE inhibitors. Optimization of the lead compounds using SBDD has resulted in a series of BACE inhibitors with a profile that was shown to inhibit Aβ production in WT and mutant APP whole cell assays. These BACE inhibitors were shown to penetrate the CNS and acutely lower brain Aβ levels in wild type and APP transgenic mice. Our results suggest that it is possible to design BACE inhibitors with the desired physical properties to overcome brain penetration issues and achieve efficacy in the CNS. These results support the utility of BACE inhibitors as a viable approach to therapeutic intervention in AD.