The  -Secretase Modulator, BMS-932481, Modulates A  Peptides in the Plasma and Cerebrospinal Fluid of Healthy Volunteers

Soares, Holly; Gąsior, Maciej; Toyn, Jeremy H.; Wang, Junsheng; Qi, Hong; Berisha, Flora; Furlong, Melissa; Raybon, Joseph; Lentz, Kimberley A.; Sweeney, Francis J.; Zheng, Naiyu; Akinsanya, Billy; Berman, R.; Thompson, Lorin A.; Olson, R. E.; Morrison, J. S.; Drexler, Dieter M.; Macor, John E.; Albright, Charlie; Ahlijanian, Michael K.; AbuTarif, Malaz

doi:10.1124/jpet.116.232256

Cited by 42 publications

(39 citation statements)

References 48 publications

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“…For example, treatment with γ-secretase modulators is associated with a selective decrease in CSF Aβ42 and Aβ40 and an increase in Aβ38 and Aβ37 [272], so these biomarkers can be used to monitor patients receiving these drugs [341]. …”

Section: Aβ Pathologymentioning

confidence: 99%

Current state of Alzheimer’s fluid biomarkers

et al. 2018

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.

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Section: Aβ Pathologymentioning

confidence: 99%

Current state of Alzheimer’s fluid biomarkers

et al. 2018

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“…As part of a single ascending dose study, healthy human subjects were given a single 900-mg oral dose of BMS-932481, or placebo, and CSF was collected via indwelling lumbar catheter at a series of time points up to 24 hours after dosing. Additional details of the clinical program are described in the accompanying manuscript by Soares et al (2016) . A β 1-42 in the BMS-932481 group gradually decreased to 50% of predose levels after 24 hours, whereas in the placebo group, there was a transient increase of ca.…”

Section: Resultsmentioning

confidence: 99%

“…Oral doses of BMS-932481 were given to human subjects in a single ascending dose study, in which subjects received doses of BMS-932481 ranging from 10 to 1200 mg. The single ascending dose study was designed and executed as a placebo-controlled, double-blinded study in healthy young subjects, and is described in detail in the accompanying manuscript by Soares et al (2016) . In one of the dose panels, longitudinal CSF samples were collected.…”

Section: Methodsmentioning

confidence: 99%

Robust Translation of -Secretase Modulator Pharmacology across Preclinical Species and Human Subjects

Toyn

Boy²,

Raybon³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The amyloid-β peptide (Aβ)—in particular, the 42–amino acid form, Aβ1-42—is thought to play a key role in the pathogenesis of Alzheimer’s disease (AD). Thus, several therapeutic modalities aiming to inhibit Aβ synthesis or increase the clearance of Aβ have entered clinical trials, including γ-secretase inhibitors, anti-Aβ antibodies, and amyloid-β precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aβ1-42 production, and may also decrease Aβ1-40 while simultaneously increasing one or more shorter Aβ peptides, such as Aβ1-38 and Aβ1-37. GSMs are particularly attractive because they do not alter the total amount of Aβ peptides produced by γ-secretase activity; they spare the processing of other γ-secretase substrates, such as Notch; and they do not cause accumulation of the potentially toxic processing intermediate, β-C-terminal fragment. This report describes the translation of pharmacological activity across species for two novel GSMs, (S)-7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (BMS-932481) and (S,Z)-17-(4-chloro-2-fluorophenyl)-34-(3-methyl-1H-1,2,4-triazol-1-yl)-16,17-dihydro-15H-4-oxa-2,9-diaza-1(2,4)-cyclopenta[d]pyrimidina-3(1,3)-benzenacyclononaphan-6-ene (BMS-986133). These GSMs are highly potent in vitro, exhibit dose- and time-dependent activity in vivo, and have consistent levels of pharmacological effect across rats, dogs, monkeys, and human subjects. In rats, the two GSMs exhibit similar pharmacokinetics/pharmacodynamics between the brain and cerebrospinal fluid. In all species, GSM treatment decreased Aβ1-42 and Aβ1-40 levels while increasing Aβ1-38 and Aβ1-37 by a corresponding amount. Thus, the GSM mechanism and central activity translate across preclinical species and humans, thereby validating this therapeutic modality for potential utility in AD.

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“…Some approaches to inhibition of enzymes, i.e., ␤and ␥-secretases involved in A␤PP cleavage, resulted in A␤ peptide formation. BACE1 is the ␤ secretase implicated in AD and inhibitors of this enzyme are verubecestat MK8931 [142,143]; AZD-3293(LY-3314814) [144,145]; AtabecestatJNJ-54861911 [146,147]; E-2609 [148]; BI-1181181 [145,149]; inhibitor of ␥-secretaseareEVP-0962 [150,151]; and BMS-932481 [152]. Recently developed compounds which prevent aggregation of A␤ are GV-971 [153]; ALZT-OP1 [154]; Phenserine [155]; Posiphen [156,157]; Scyllo-Inositol [158,159]; ALZ-801 [160]; SAN-61 [161] and Exebryl-1 [162].…”

Section: Anti-amyloid Drugs In Clinical Trialsmentioning

confidence: 99%

Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings

Duggal

Mehan

2019

ADR

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Neuronal microtubule (MT) tau protein provides cytoskeleton to neuronal cells and plays a vital role including maintenance of cell shape, intracellular transport, and cell division. Tau hyperphosphorylation mediates MT destabilization resulting in axonopathy and neurotransmitter deficit, and ultimately causing Alzheimer's disease (AD), a dementing disorder affecting vast geriatric populations worldwide, characterized by the existence of extracellular amyloid plaques and intracellular neurofibrillary tangles in a hyperphosphorylated state. Pre-clinically, streptozotocin stereotaxically mimics the behavioral and biochemical alterations similar to AD associated with tau pathology resulting in MT assembly defects, which proceed neuropathological cascades. Accessible interventions like cholinesterase inhibitors and NMDA antagonist clinically provides only symptomatic relief. Involvement of microtubule stabilizers (MTS) prevents tauopathy particularly by targeting MT oriented cytoskeleton and promotes polymerization of tubulin protein. Multiple in vitro and in vivo research studies have shown that MTS can hold substantial potential for the treatment of AD-related tauopathy dementias through restoration of tau function and axonal transport. Moreover, anti-cancer taxane derivatives and epothiolones may have potential to ameliorate MT destabilization and prevent the neuronal structural and functional alterations associated with tauopathies. Therefore, this current review strictly focuses on exploration of various clinical and pre-clinical features available for AD to understand the neuropathological mechanisms as well as introduce pharmacological interventions associated with MT stabilization. MTS from diverse natural sources continue to be of value in the treatment of cancer, suggesting that these agents have potential to be of interest in the treatment of AD-related tauopathy dementia in the future.

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The -Secretase Modulator, BMS-932481, Modulates A Peptides in the Plasma and Cerebrospinal Fluid of Healthy Volunteers

Cited by 42 publications

References 48 publications

Current state of Alzheimer’s fluid biomarkers

Current state of Alzheimer’s fluid biomarkers

Robust Translation of -Secretase Modulator Pharmacology across Preclinical Species and Human Subjects

Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings

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