Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the major cause of dementia in the elderly and an unmet clinical challenge. A variety of therapies that are currently under development are directed to the amyloid cascade. Indeed, the accumulation and toxicity of amyloid-β (Aβ) is believed to play a central role in the etiology of the disease, and thus rational interventions are aimed at reducing the levels of Aβ in the brain. Targeting β-site amyloid precursor protein-cleaving enzyme (BACE)-1 represents an attractive strategy, as this enzyme catalyzes the initial and rate-limiting step in Aβ production. Observation of increased levels of BACE1 and enzymatic activity in the brain, cerebrospinal fluid, and platelets of patients with AD and mild cognitive impairment supports the potential benefits of BACE1 inhibition. Numerous potent inhibitors have been generated, and many of these have been proved to lower Aβ levels in the brain of animal models. Over 10 years of intensive research on BACE1 inhibitors has now culminated in advancing half a dozen of these drugs into human trials, yet translating the in vitro and cellular efficacy of BACE1 inhibitors into preclinical and clinical trials represents a challenge. This review addresses the promises and also the potential problems associated with BACE1 inhibitors for AD therapy, as the complex biological function of BACE1 in the brain is becoming unraveled.

Synthesis of beta‐site amyloid precursor protein‐cleaving enzyme 1 inhibitors BI 1147560 and BI 1181181 labeled with carbon‐14 and deuterium

“…1 H NMR (CDCl 3 , 400 MHz) δ: 7.15-7.30 (m, 10H), 4.12 (m, 4H), 3.61 (s, 1H), 3.52 (s, 4H), 1.20 (t, J = 7.56 Hz, 6H). 13 The flask containing the malonate derivative was rinsed with THF (20 mL) and added to the reaction flask. The mixture was warmed to room temperature and stirred for 14 h. The mixture was cooled in an ice bath, and Na 2 SO 4 (20.7 g, 146 mmol) and water (20 mL) were added in small portions.…”

“…For example, targeting beta‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) looks like a promising target as this enzyme catalyzes the initial rate‐limiting step in amyloid beta productions. Drugs that block this enzyme in theory would prevent the buildup of β‐amyloid and may help slow or stop this disease 11–15 . Many pharmaceutical companies invested in this strategy; unfortunately, BACE inhibitors have failed to produce significant progress in treating Alzheimer's disease 16–18 .…”

“…Drugs that block this enzyme in theory would prevent the buildup of β-amyloid and may help slow or stop this disease. [11][12][13][14][15] Many pharmaceutical companies invested in this strategy; unfortunately, BACE inhibitors have failed to produce significant progress in treating Alzheimer's disease. [16][17][18] In this manuscript, we report the synthesis of two potent BACE1 inhibitors 19 labeled with carbon-14 and with deuterium as tools for drug metabolism, pharmacokinetics, bioanalytics, and other studies (Figure 1).…”

Functional Foods: An Approach to Modulate Molecular Mechanisms of Alzheimer’s Disease

“…It is also known that oxidative stress favors Aβ production by stimulating the activity of Beta-Site APP-Cleaving Enzyme (BACE). Plaque formation occurs only when APP protein comes into contact with BACE, which cleavages APP allowing it to precipitate in the form of plaques [116,117]. All these data constitute an element in favor of the use of antioxidants for the prophylaxis and treatment of the disease.…”

The Anti-Aggregative Peptide KLVFF Mimics Aβ1-40 in the Modulation of Nicotinic Receptors: Implications for Peptide-Based Therapy

“…Moreover, the protein has a hormetic profile that oscillates between physiological and pathological effects that are not yet fully clarified [ 7 ]. Accordingly, the idea of blocking enzymatic production has not produced convincing results [ 8 ]. The need to protect patients from physiological effects has prompted researchers to investigate the reasons for pathological accumulation and aggregation [ 9 , 10 ].…”