We report the design and synthesis of a series of BACE1 inhibitors incorporating mono- and bicyclic 6-substituted 2-oxopiperazines as novel P1′ and P2′ ligands and isophthalamide derivative as P2-P3 ligands. Among mono-substituted 2-oxopiperazines, inhibitor 5a with N-benzyl-2-oxopiperazine and isophthalamide showed potent BACE1 inhibitory activity (Ki = 2 nM). Inhibitor 5g, with N-benzyl-2-oxopiperazine and substituted indole-derived P2-ligand showed a reduction in potency. The X-ray crystal structure of 5g-bound BACE1 was determined and used to design a set of disubstituted 2-oxopiperazines and bicyclic derivatives that were subsequently investigated. Inhibitor 6j with an oxazolidinone derivative showed a BACE1 inhibitory activity of 23 nM and cellular EC50of 80 nM.

Ghosh, A.K., Brindisi, M., Yen, Y., Cã¡rdenas, E.L., Ella-Menye, J., Kumaragurubaran, N., et al. (2017). Design, synthesis, and X-ray structural studies of BACE-1 inhibitors containing substituted 2-oxopiperazines as P1 '-P2 ' ligands. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 27(11), 2432-2438 [10.1016/j.bmcl.2017.04.011].

Design, synthesis, and X-ray structural studies of BACE-1 inhibitors containing substituted 2-oxopiperazines as P1 '-P2 ' ligands

Brindisi, Margherita;
2017-01-01

Abstract

We report the design and synthesis of a series of BACE1 inhibitors incorporating mono- and bicyclic 6-substituted 2-oxopiperazines as novel P1′ and P2′ ligands and isophthalamide derivative as P2-P3 ligands. Among mono-substituted 2-oxopiperazines, inhibitor 5a with N-benzyl-2-oxopiperazine and isophthalamide showed potent BACE1 inhibitory activity (Ki = 2 nM). Inhibitor 5g, with N-benzyl-2-oxopiperazine and substituted indole-derived P2-ligand showed a reduction in potency. The X-ray crystal structure of 5g-bound BACE1 was determined and used to design a set of disubstituted 2-oxopiperazines and bicyclic derivatives that were subsequently investigated. Inhibitor 6j with an oxazolidinone derivative showed a BACE1 inhibitory activity of 23 nM and cellular EC50of 80 nM.
Ghosh, A.K., Brindisi, M., Yen, Y., Cã¡rdenas, E.L., Ella-Menye, J., Kumaragurubaran, N., et al. (2017). Design, synthesis, and X-ray structural studies of BACE-1 inhibitors containing substituted 2-oxopiperazines as P1 '-P2 ' ligands. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 27(11), 2432-2438 [10.1016/j.bmcl.2017.04.011].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1030061