Design and Synthesis of Inhibitors Targeting BACE-1, an Aspartic Protease Involved in the Pathogenesis of Alzheimer’s Disease

"Anyone who has never made a mistake has never tried anything new." Abstract Alzheimer's disease (AD) is the most common form of dementia, occurring in an estimated 24 million people worldwide. Accumulation of amyloid-β peptides leads to development of plaques in the brain, which eventually stimulates hyperphosphorylation of tau proteins leading to tangles. This is believed to play a crucial role in the pathology of AD. The amyloid-β peptides are formed when the amyloid precursor protein (APP) is cleaved first by the human aspartic protease BACE-1 and then by the protease γ-secretase. BACE-1 catalyzes the rate-limiting step in this sequence, and hence it has emerged as an important therapeutic drug target. The research reported in this thesis is focused on the design and synthesis of BACE-1 inhibitors, where the synthetic work involves development of both acyclic and cyclic inhibitors. Initially, a series of linear inhibitors incorporating substituted cyclopentanes in the P2 position were synthesized and evaluated in an attempt to find a replacement for the widely used isophthalamide moiety, and this endeavor generated an inhibitor with activity in the nanomolar range. In the second study, a series of hydroxyethylene-based inhibitors with extended P1 substituents was synthesized and evaluated, which resulted in several truncated inhibitors also with activities in the nanomolar range. The third investigation targeted a series of P1-P3-linked hydroxyethylamine-based macrocyclic inhibitors and provided several highly potent compounds, however it did not deliver high cell permeability inhibitors. In addition, two inhibitors were co-crystallized with BACE-1 to provide X-ray crystal structures, which enabled analysis of the binding properties of these inhibitors. In the final study, the P2/P3 macrocyclic amide moiety and the P1-P3 ether oxygen bridge from the previous work were replaced with a keto functionality and a carbon, respectively, in an attempt to improve the permeability properties whilst maintaining the beneficial potencies of this class of macrocyclic inhibitors. The compounds synthesized did indeed display enhanced cell permeability properties, but this approach resulted in decreased potency. In short, this thesis presents several novel BACE-1 inhibitors, discusses the synthetic strategies, and reports biological data on the target compounds. List of papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals (I–IV): Exploration of the active site of BACE-1: Design and synthesis of inhibitors incorporating substituted cyclopentanes in the P2 position Design and synthesis of hydroxyethylene-based BACE-1 inhibitors incorporating extended P1 substituents Highly …