Design, synthesis and SAR of potent statin-based β-secretase inhibitors: Exploration of P1 phenoxy and benzyloxy residues

MEDI 295

Marcus Bäck, marba@ifm.liu.se1, Jonas Nyhlén2, Ingemar Kvarnström, ink@ifm.liu.se1, Åsa Rosenquist, Asa.Rosenquist@medivir.com3, and Bertil Samuelsson, bertil.samuelsson@medivir.se3. (1) Department of Chemistry, Linköping University, Campus Valla, S-58183 Linköping, Sweden, (2) Department of Organic Chemistry, Stockholm University, Arrhenius Laboratory, SE-10691 Stockholm, Sweden, (3) Medivir AB, Lunastigen 7, S-14144 Huddinge, Sweden
The human aspartic protease, β-secretase (BACE), is generally considered to play an initiating role in the neurodegenerative cascade ultimately leading to Alzheimer's disease (AD). The amyloid precursor protein (APP) is cleaved by different proteases along two major pathways, the α-secretase pathway and the amyloid forming β-secretase (BACE) pathway. The amyloid forming pathway is dependent on two proteolytic cleavages perfomed by β-secretase and γ-secretase, resulting in the release of amyloid-β40 (Aβ40) and the insoluble pathogenic amyloid-β42 (Aβ42). In this study we present several potent and promising BACE inhibitors, displaying low nanomolar activity, which were identified from a series of statine-based inhibitors incorporating novel methylphenyloxy- and methylbenzyloxy residues in the P1 position.

 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007