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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 Ki 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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