Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C17H17F2N5O3S |
Molecular Weight | 409.41 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CN1C(N)=N[C@@](C)(CS1(=O)=O)C2=CC(NC(=O)C3=CC=C(F)C=N3)=CC=C2F
InChI
InChIKey=YHYKUSGACIYRML-KRWDZBQOSA-N
InChI=1S/C17H17F2N5O3S/c1-17(9-28(26,27)24(2)16(20)23-17)12-7-11(4-5-13(12)19)22-15(25)14-6-3-10(18)8-21-14/h3-8H,9H2,1-2H3,(H2,20,23)(H,22,25)/t17-/m0/s1
Verubecestat (MK 8931) is a potentially first-in-class, potent β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor being developed by Merck. Verubecestat (MK-8931) is a selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys. Verubecestat was under investigation for the treatment of Alzheimer's disease, prodromal Alzheimer's disease, and amnestic mild cognitive impairment. In November 2013, Merck began the APECS trial in 1,500 participants with prodromal AD, aka mild cognitive impairment due to AD (aMCI). These patients have measurable cognitive deficits and a positive PET scan with the newly FDA-approved amyloid tracer flutemetamol, but are not functionally impaired. APECS compared 12 and 40 mg once-daily doses to placebo; treatment was to last for two years. APECS usef change from baseline on the Clinical Dementia Rating Sum of Boxes (CDR-SB), a continuous measure, as its primary outcome. Secondary outcomes evaluated a range of newer measures, including a cognitive composite, CSF tau, brain imaging of hippocampal volume and amyloid load, and others. This trial was being conducted in more than 90 locations worldwide; it completed enrollment in November 2016 and was expected to complete data collection for its primary outcome in 2019. In February 2018, APECS was discontinued and Merck no longer listed verubecestat in its research pipeline. APECS participants on 40 mg verubecestat scored worse than the placebo group on the CDR-SB and ADAS-Cog13 starting at 13 weeks. The effect was small and did not progress over time. The 12 mg treatment group also performed slightly worse than controls, with the difference reaching significance at scattered time points.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL4822 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24556009 |
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Target ID: CHEMBL4822 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23412139 |
7.8 nM [Ki] |
PubMed
Title | Date | PubMed |
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Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Aβ Reduction. | 2012 Nov 8 |
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Synthesis of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer's Disease. | 2016 Nov 18 |
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The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients. | 2016 Nov 2 |
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Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-AβPPswe Mice Without Inducing Microhemorrhage. | 2017 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://www.alzforum.org/therapeutics/verubecestat
12, 40, or 60 mg/day of Verubecestat (MK 8931) given as once-daily tablets to placebo in people with mild to moderate AD.
Route of Administration:
Oral
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C471
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C1509
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ACTIVE MOIETY
METABOLITE INACTIVE (PARENT)
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