Vom Fragment-Screening zu Leads für neue Alzheimer-Medikamente

Abstract

viii Abstract Alzheimer’s disease (AD) is a severe neurodegenerative disorder and the most common cause of dementia in elderly people. To this day, there is no cure for AD. Existing treatments offer – if at all – only small therapeutic benefits, therefore, there is an urgent need for new medicines.Alzheimer’s disease (AD) is a severe neurodegenerative disorder and the most common cause of dementia in elderly people. To this day, there is no cure for AD. Existing treatments offer – if at all – only small therapeutic benefits, therefore, there is an urgent need for new medicines. According to the amyloid hypothesis of AD, accumulation of amyloid -peptide (A) is the primary influence driving AD pathogenesis. A is formed by the sequential processing of the amyloid precursor protein (APP) by -secretase (BACE1) and -secretase. Being the key enzyme that initiates the formation of A, BACE1 represents an attractive drug target. BACE1 is a monomeric aspartic protease. The active site is located in the cleft between the N-terminal and the C-terminal lobe and is covered by a flexible flap (Fig. 1). Fig. 1: Ribbon representation of BACE1. N-terminal lobe shown in blue, C-terminal lobe in red, flap and ligand 8 in green (PDB Code: 3BUH). A fragment screening, performed by F. Hoffmann-La Roche, revealed that tyramine 9 binds to the active site of BACE1 with a high ligand efficiency (LE = 0.37, KD = 2000 M). Further tyramine derivatives (e.g. 8) as well as an indolamine derivative (10) with improved binding affinities have been discovered by Roche, using surface plasmon resonance measurements (Biacore). X-ray crystal structures of BACE1 complexed with several of these compounds showed that the amine moiety of the tyramine fragments forms hydrogen bonds to the catalytic dyad and the residues located in ortho-position of the phenol moiety occupy the