Machauer R.
*
et al.
Novartis Pharma AG, Basel, Switzerland
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.
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.
