Design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand.

Bioorg Med Chem Lett 2018 08 26;28(15):2605-2610. Epub 2018 Jun 26.

Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Biochemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, United States.

We describe the design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors containing bicyclic isoxazoline carboxamides as the P3 ligand in combination with methyl cysteine, methylsulfonylalanine and Boc-amino alanine as P2 ligands. Inhibitor 3a displayed a BACE1 K value of 10.9 nM and EC of 343 nM. The X-ray structure of 3a bound to the active site of BACE1 was determined at 2.85 Å resolution. The structure revealed that the major molecular interactions between BACE1 and the bicyclic tetrahydrofuranyl isoxazoline heterocycle are van der Waals in nature.

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http://dx.doi.org/10.1016/j.bmcl.2018.06.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085084PMC
August 2018
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