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 Kivalue of 10.9 nM and EC50of 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.

Ghosh, A.K., Ghosh, K., Brindisi, M., Lendy, E.K., Yen, Y.-., Kumaragurubaran, N., et al. (2018). Design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 28(15), 2605-2610 [10.1016/j.bmcl.2018.06.045].

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

Brindisi M.;
2018-01-01

Abstract

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 Kivalue of 10.9 nM and EC50of 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.
Ghosh, A.K., Ghosh, K., Brindisi, M., Lendy, E.K., Yen, Y.-., Kumaragurubaran, N., et al. (2018). Design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 28(15), 2605-2610 [10.1016/j.bmcl.2018.06.045].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1079856