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.

Anterior fixation devices for the thoracolumbar spine have gained wide acceptance as viable alternatives to long-segment posterior fixation in cases of thoracolumbar spine trauma. This review was undertaken to evaluate the safety and efficacy of the Synthes anterior thoracolumbar locking plate (ATLP) system. Over a 3-year period, 31 patients with unstable traumatic fractures of the thoracolumbar spine underwent corpectomy, placement of a structural bone graft, and anterior fixation in which the Synthes ATLP system was used. Long-term follow-up data were obtained in 29 patients. Two patients were lost to follow up, one at 4 months and the other at 1 year. In the remaining patients, the average length of follow up was 20 months. In all patients radiographic evidence of solid bone fusion was demonstrated on follow-up plain x-ray films, and there were no signs or symptoms of pseudarthrosis. No patient suffered neurological deterioration as a result of surgery, and there was relatively little morbidity associated with this plating system. To date, none of the patients in this study has developed any delayed complications related to the fixation device. In one patient, who had sustained a severe flexion injury, loosening of the anterior fixation device occurred, and the patient developed progressive kyphosis, which required a posterior stabilization procedure. These results appear slightly better than those obtained in published studies in which other anterior plating systems were used, indicating that this system is safe and effective in the treatment of unstable fractures of the thoracolumbar spine.

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