Discovery of S3-Truncated, C‑6 Heteroaryl Substituted Aminothiazine β‑Site APP Cleaving Enzyme‑1 (BACE1) Inhibitors

Truncation
of the S3 substituent of the biaryl aminothiazine 2,
a potent BACE1 inhibitor, led to a low molecular weight
aminothiazine 5 with moderate activity. Despite its moderate
activity, compound 5 demonstrated significant brain Aβ
reduction in rodents. The metabolic instability of 5 was
overcome by the replacement of the 6-dimethylisoxazole, a metabolic
soft spot, with a pyrimidine ring. Thus, truncation of the S3 substituent
represents a viable approach to the discovery of orally bioavailable,
brain-penetrant BACE1 inhibitors.