Structure-based design and synthesis of novel P2/P3 modified, non-peptidic β-secretase (BACE-1) inhibitors

ArticleinBioorganic & medicinal chemistry letters 20(6):1924-7 · February 2010with6 Reads
Impact Factor: 2.42 · DOI: 10.1016/j.bmcl.2010.01.139 · Source: PubMed


    Starting from peptidomimetic BACE-1 inhibitors, the P2 amino acid including the P2/P3 peptide bond was replaced by a rigid 3-aminomethyl cyclohexane carboxylic acid. Co-crystallization revealed an unexpected binding mode with the P3/P4 amide bond placed into the S3 pocket resulting in a new hydrogen bond interaction pattern. Further optimization based on this structure resulted in highly potent BACE-1 inhibitors with selectivity over BACE-2 and cathepsin D.