Secretase BACE

Figure 11.1 The amyloid hypothesis in Alzheimer s disease. The transmembrane protein amyloid precursor protein (APP) is cleaved first by f> -secretase (BACE), then by y -secretase. The resulting peptidic fragment, AfSAO/42, is liberated, leading to plaque accumulation. These plaques are associated with neuronal degeneration.

A high-throughput screening (HTS) campaign to identify S-secretase (BACE-1) inhibitors provided compound 1 (Fig. 1) as a promising new hit which was quickly optimized to compound 2 with the aid of an Ugi MCR [10]. Although compound... 

Moitessier, N., Therrien, E., Hanessian, S. A method for induced-fit docking, scoring, and ranking of flexible ligands. Application to peptidic and pseudopeptidic beta-secretase (BACE 1) inhibitors. J. Med. Chem. 2006, 49(20), 5885. 

In order to illustrate the theoretical considerations of a fragment screening effort we selected two targets, chymase and (3-secretase (BACE) for a more detailed discussion of the experimental set-up. 

Alzheimer disease is characterized by the formation of amyloid plaques composed by accumulated neurotoxic p-amyloid peptides. These peptides are generated from amyloid precursor protein by proteolytic processing implicating the protease p-secretase BACE-1. The proteolytic degradation of the amyloid precursor protein can be modulated by inhibition of the BACE-1. Boons et synthesized well-defined HS oligosaccharides and found that one tetrasaccharide was able to inhibit it well. Tyler et al synthesized a library of 16 HS hexa- to dodecasaccharides. Screening of... 

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