P4‐196: The novel BACE inhibitor MK‐8931 dramatically lowers cerebrospinal fluid Aβ peptides in healthy subjects following single‐ and multiple‐dose administration

Forman, Mark S.; Palcza, John; Tseng, Jack; Leempoels, J.; Ramael, Steven; Han, David; Jhee, Stanford; Ereshefsky, Larry; Tanen, Michael; Laterza, Omar; Dockendorf, Marissa; Krishna, Gopal; Ma, Lei; Wagner, John A.; Troyer, Matthew D.

doi:10.1016/j.jalz.2012.05.1900

Cited by 39 publications

(27 citation statements)

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“…Noteworthy is also that the magnitude of the effect on both sAPP␤ SWE and sAPP␣ does not change with treatment length. Intriguingly, brain A␤40/42 reductions in this Tg2576 mouse model, independent of being endogenous or derived from the overexpressed human APP SWE , only showed a reduction on soluble A␤40/42 after repeated dosing for 7 d and on insoluble A␤40/42 when treated for 28 d. These finding are in line with the observations made by Fukumoto et al (2010) where they demonstrated effects on Tris-soluble A␤ in the brain of young Tg2576 mice after 7 weeks of oral administration of a BACE1 inhibitor and on insoluble (FA) A␤ in 13-month-old Tg2576 mice after 6 months of treatment. demonstrated effects on interstitial fluid A␤40 in young Tg2576 mice after an acute dose of a BACE1 inhibitor but only observed effects on brain extracts after long-term treatment.…”

Section: Discussionsupporting

confidence: 89%

“…These observations raise concerns whether complete inhibition of BACE1 in a chronic setting is safe and may have impli-cations for the development of BACE1 inhibitors for therapeutic use. Several BACE1 inhibitors are currently in clinical development and have reported CSF A␤ lowering in Phase I clinical studies (May et al, 2011;Forman et al, 2012;. This is a promising first step to testing the potential of BACE1 inhibition as modifying the course of AD.…”

Section: Introductionmentioning

confidence: 99%

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AZ-4217: A High Potency BACE Inhibitor Displaying Acute Central Efficacy in Different In Vivo Models and Reduced Amyloid Deposition in Tg2576 Mice

Eketjäll

Janson

Jeppsson

et al. 2013

Journal of Neuroscience

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A␤, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). ␤-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to A␤ peptides. Small molecule BACE1 inhibitors are expected to decrease A␤-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD. BACE1 inhibition thus addresses a key mechanism in AD and its potential as a therapeutic target is currently being addressed in clinical studies. Here, we report the discovery and the pharmacokinetic and pharmacodynamic properties of BACE1 inhibitor AZ-4217, a high potency compound (IC 50 160 pM in human SH-SY5Y cells) with an excellent in vivo efficacy. Central efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in an APP transgenic mouse model of cerebral amyloidosis (Tg2576). Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of A␤ production does lower amyloid deposition in 12-month-old Tg2576 mice. These results strongly support BACE1 inhibition as concretely impacting amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

AZ-4217: A High Potency BACE Inhibitor Displaying Acute Central Efficacy in Different In Vivo Models and Reduced Amyloid Deposition in Tg2576 Mice

Eketjäll

Janson

Jeppsson

et al. 2013

Journal of Neuroscience

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“…66 Safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple (daily for 14 days) doses were evaluated. MK-8931 seems to be generally well tolerated, and no serious adverse events were reported.…”

Section: Bace1 Inhibitor Drugs For Alzheimer’s Diseasementioning

confidence: 99%

Targeting the β secretase BACE1 for Alzheimer's disease therapy

Yan¹,

Vassar²

2014

The Lancet Neurology

548

432

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The β secretase, widely known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), initiates the production of the toxic amyloid β (Aβ) that plays a crucial early part in Alzheimer’s disease pathogenesis. BACE1 is a prime therapeutic target for lowering cerebral Aβ concentrations in Alzheimer’s disease, and clinical development of BACE1 inhibitors is being intensely pursued. Although BACE1 inhibitor drug development has proven challenging, several promising BACE1 inhibitors have recently entered human clinical trials. The safety and efficacy of these drugs are being tested at present in healthy individuals and patients with Alzheimer’s disease, and will soon be tested in individuals with presymptomatic Alzheimer’s disease. Although hopes are high that BACE1 inhibitors might be efficacious for the prevention or treatment of Alzheimer’s disease, concerns have been raised about potential mechanism-based side-effects of these drugs. The potential of therapeutic BACE1 inhibition might prove to be a watershed in the treatment of Alzheimer’s disease.

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“…Results of Phase I clinical studies demonstrated that MK-8931 resulted in a dose-dependent and sustained reduction in CSF Aβ levels by greater than 90% in healthy volunteers without dose-limiting side effects [40]. Based on these results, global, multicenter Phase II/III clinical trials are conducted to evaluate the safety and efficacy of MK-8931 versus placebo in patients with mild-to-moderate AD.…”

Section: β-Secretase Inhibitorsmentioning

confidence: 99%

Advances in Recent Patent and Clinical Trial Drug Development for Alzheimer’s Disease

et al. 2014

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease, involving a large number of genes, proteins and their complex interactions. Currently, no effective therapeutic agents are available to either stop or reverse the progression of this disease, likely due to its polygenic nature. The complicated pathophysiology of AD remains unresolved. Although it has been hypothesized that the amyloid β cascade and the hyper-phosphorylated tau protein may be primarily involved, other mechanisms, such as oxidative stress, deficiency of central cholinergic neurotransmitter, mitochondrial dysfunction and inflammation have also been implicated. The main focus of this review is to document current therapeutic agents in clinical trials and patented candidate compounds under development based on their main mechanisms of action. It also discusses the relationship between the recent understanding of key targets and the development of potential therapeutic agents for the treatment of AD.

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P4‐196: The novel BACE inhibitor MK‐8931 dramatically lowers cerebrospinal fluid Aβ peptides in healthy subjects following single‐ and multiple‐dose administration

Cited by 39 publications

References 0 publications

AZ-4217: A High Potency BACE Inhibitor Displaying Acute Central Efficacy in Different In Vivo Models and Reduced Amyloid Deposition in Tg2576 Mice

AZ-4217: A High Potency BACE Inhibitor Displaying Acute Central Efficacy in Different In Vivo Models and Reduced Amyloid Deposition in Tg2576 Mice

Targeting the β secretase BACE1 for Alzheimer's disease therapy

Advances in Recent Patent and Clinical Trial Drug Development for Alzheimer’s Disease

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