BACE

Scheme 7.13. TADDOL-baced phocphoramldlte llgandc In the catalytic 1,4-addition.

BACE-2 IC50 2.3 pM CathD IC50 18.9 pM Cell Ap total ED50 3.8 pM... 

BACE-1 (p-secretase) is one of the enzymes involved in breaking down APP to produce Ap (amyloid p-peptide, Ap40>42), the protein that eventually oligomerizes to form Ap plaques, the hallmark of Alzheimer s disease (AD). Thus an agent that... 

A universal postmortem hallmark of Alzheimer s disease (AD) is the presence of amyloid plaques in the brain. These plaques are mainly composed of a 39 to 42 amino acid peptide, referred to as A0 peptide, that is excised from a precursor protein, amyloid precursor protein (APP), by the sequential action of two proteases (Olsen et al., 2001). The first of the two cleavages of APP occurs at a site within the APP protein that is termed the P-site, and BACE has been clearly determined to be the enzyme responsible for this cleavage event. A small portion of the AD patient... 

With this information in hand, initial attempts to generate BACE inhibitors used the peptidic Swedish variant substrate as a starting point and substituted the scissile amide bond with a statine. For example, Sinha et al. (1999) synthesized a P10-P4 1 Swedish variant peptide with a statine moiety in place of the Pl-Pl scissile bond and showed that this peptidomimetic displayed an IC50 of 40 pM for inhibition of BACE. Optimization of this inhibitor was then performed by systematic replacement of amino acid side chains. Replacement of the PE Asp residue by Val reduced the IC50 for BACE inhibition to 30 nM this inhibitor is referred to here as Stat-Val. 

BACE-1 IC5Q= 8 nM BACE-1 IC50 = 4 nM BACE-1 ICjq — 4 nM... 

BACE-2 IC50 = 4270 nM BACE-2 IC5o = 785 nM BACE-2 IC50= 177 nM... 

Vassar, R., Bennett, B. D., Babu-Khan, S. et al. P-secretase cleavage of Alzheimer s amyloid precusor protein by the transmembrane aspartic protease BACE. Science 286 735-741, 1999. 

Haass, C. Take five—BACE and the gamma-secretase quartet conduct Alzheimer s amyloid beta-peptide generation. EMBO J. 23 483-488, 2004. 

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