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

Abstract

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.

Safety, Tolerability, and Pharmacokinetics of the β‐Site Amyloid Precursor Protein‐Cleaving Enzyme 1 Inhibitor Verubecestat (MK‐8931) in Healthy Elderly Male and Female Subjects

“…The safety and PK of verubecestat were previously established in healthy young adults . Furthermore, reductions in Aβ in CSF by verubecestat have been demonstrated in healthy adults and subjects with AD and found to be consistent with those in animal models . As AD is predominantly a disease of the elderly, the current study was designed to investigate the safety, tolerability, and PK of verubecestat in elderly subjects relative to young male subjects and assess the impact of sex on verubecestat PK.…”

“…The amyloid hypothesis implicates Aβ peptides in the etiology of AD, and it is hypothesized that Aβ blockade may confer beneficial effects in AD . Thus, preventing generation of Aβ peptides by inhibition of BACE1 (the first step in the processing of APP to Aβ) is a logical target to test the amyloid hypothesis, and the BACE1 inhibitor verubecestat is in clinical development for AD . The safety and PK of verubecestat were previously established in healthy young adults .…”

“…Verubecestat (MK‐8931) is a potent inhibitor of BACE1 . In rats and monkeys, verubecestat administration resulted in a marked dose‐dependent reduction of Aβ peptides in plasma and cerebrospinal fluid (CSF) and the cortex .…”

Pharmacokinetics and Pharmacodynamics of the BACE1 Inhibitor Verubecestat (MK‐8931) in Healthy Japanese Adults: A Randomized, Placebo‐Controlled Study

“…Inhibition of BACE1 blocks the amyloidogenic pathway at its initiation, potentially stopping all downstream processes, in particular the production of potentially toxic Aβ peptides . Verubecestat (MK‐8931) is a potent, selective, competitive inhibitor of BACE1 . In rats and monkeys, verubecestat administration resulted in a marked dose‐dependent reduction in the production of Aβ peptides in plasma, cerebrospinal fluid (CSF), and cortex .…”

“…13 Verubecestat (MK-8931) is a potent, selective, competitive inhibitor of BACE1. 14 In rats and monkeys, verubecestat administration resulted in a marked dose-dependent reduction in the production of Aβ peptides in plasma, cerebrospinal fluid (CSF), and cortex. 15 Similarly, in healthy human subjects and patients with AD, single and multiple doses of orally administered verubecestat were generally well tolerated and reduced plasma and CSF levels of the amyloid precursor protein metabolites Aβ40, Aβ42, and soluble β fragment of amyloid precursor protein (sAPPβ).…”