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

Department of Chemistry, Université de Montréal, Montréal, Canada.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 02/2010; 20(6):1924-7. 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.

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    • "Unfortunately, testing of compound 42 in an in vitro model (MDCK cells stably transfected with the gene for the human Pgp transporter), resulted in a high efflux ratio (BA/AB = 97). Therefore, the modification of the P2/P3 amide region did not overcome this challenging problem (Hanessian et al., 2010). "
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