Discovery of the 3‑Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)–A β‑Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer’s Disease

Verubecestat 3 (MK-8931), a diaryl amide-substituted
3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity
β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor
currently undergoing Phase 3 clinical evaluation for the treatment
of mild to moderate and prodromal Alzheimer’s disease. Although
not selective over the closely related aspartyl protease BACE2, verubecestat
has high selectivity for BACE1 over other key aspartyl proteases,
notably cathepsin D, and profoundly lowers CSF and brain Aβ
levels in rats and nonhuman primates and CSF Aβ levels in humans.
In this annotation, we describe the discovery of 3, including
design, validation, and selected SAR around the novel iminothiadiazinane
dioxide core as well as aspects of its preclinical and Phase 1 clinical
characterization.