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

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 K_i value of 10.9 nM and EC₅₀ 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.

SUBMITTER: Ghosh AK

PROVIDER: S-EPMC6085084 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Ghosh Arun K AK Ghosh Koena K Brindisi Margherita M Lendy Emma K EK Yen Yu-Chen YC Kumaragurubaran Nagaswamy N Huang Xiangping X Tang Jordan J Mesecar Andrew D AD

Bioorganic & medicinal chemistry letters 20180626 15

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<sub>i</sub> value of 10.9 nM and EC<sub>50</sub> 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 in ...[more]

PMID: 29970308

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