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DOI: 10.1055/s-0040-1720423
Synthesis of β-Secretase Inhibitor NB-360
Synthesis of the Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor NB-360.
J. Med. Chem. 2021;
64: 4677-4696
DOI: 10.1021/acs.jmedchem.0c02143.
Key words
NB-360 - β-secretase 1 inhibitor - Alzheimer's disease - aziridine ring opening - 1,4-oxazine ring formation
Significance
β-Secretase 1 (BACE1) is an aspartic acid protease located primarily in neurons. It is the major β-secretase involved in the generation of amyloid-β peptides (Aβ) and their subsequent aggregation to form plaques associated with the onset of Alzheimer’s disease. NB-360 is the latest in a long line of similar amidine-based BACE1 inhibitors that have hitherto failed in phase II/III clinical trials.
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Comment
The two quaternary centers in NB-360 shielded the amidine and ether oxygen from undesired chemical and metabolic transformations. The key step in the most practical route to the 1,4-oxazine K entailed the nucleophilic opening of the chiral N-sulfonylaziridine F with the chiral alkoxide derived from E in the presence of potassium tert-butoxide in DMF at 35 °C.
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Publication History
Article published online:
17 June 2021
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