1286770-55-5

Usage

Uses

Used in Pharmaceutical Industry:
MK-8931 is used as a BACE1 inhibitor for the treatment of Alzheimer's disease. Its application aims to reduce the production of amyloid-beta peptides, which are implicated in the development and progression of the disease. By targeting BACE1, MK-8931 may help slow down or halt the cognitive decline associated with Alzheimer's, offering a promising therapeutic option for patients suffering from this neurodegenerative disorder.

Biological Activity

ki: 2.2 and 3.4 nm for human and mouse bace1, respectivelyverubecestat (mk-8931) is a bace1 inhibitor.β-amyloid (aβ) peptides are regarded to be involved in the etiology of ad. bace1 is required for the aβ production, and bace1 inhibition is therefore an promising target for the ad treatment.

in vitro

verubecestat has been identified as a potent inhibitor of both human and mouse bace1 and verubecestat could also inhibit the production of ab40, ab42, and sappb in human cells with similar potency. verubecestat was also found to be a potent inhibitor of purified human bace2. moreover, verubecestat was essentially inactive with over 45,000-fold selectivity in the purified human aspartyl proteases cathepsin d, cathepsin e, and pepsin and had a very weak inhibitor of purified human renin with 15,000-fold selectivity. in addition, verubecestat was also found to have minimal or no activity against various tested receptors, ion channels, transporters, as well as enzymes [1].

in vivo

verubecestat could reduce plasma, cerebrospinal fluid, and brain concentrations of aβ40, aβ42, and sappβ after acute and chronic administration to both rats and monkeys. moreover, the chronic treatment of rats and monkeys with verubecestat at exposures >40-fold higher than those tested in

references

[1] kennedy me et al. the bace1 inhibitor verubecestat (mk-8931) reduces cns β-amyloid in animal models and in alzheimer's disease patients. sci transl med.2016 nov 2;8(363):363ra150.

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Relevant academic research and scientific papers

Characterization of a Unique Co-crystal of the BACE1 Inhibitor Verubecestat and a Reaction Intermediate: Implications for the Development of a Commercial Manufacturing Process

Verubecestat is an inhibitor of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) that is currently under clinical evaluation for the treatment of prodromal Alzheimer's disease. This article describes the characterization of a co-crystal composed of a HBr salt of verubecestat and a HBr salt of a reaction intermediate as the components. This unique co-crystal was formed during production of a multikilogram batch of verubecestat. The impact of this observation is discussed, followed by the description of a modified procedure that served to prevent the formation of this highly unusual crystalline material.

Synthesis of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer's Disease

Verubecestat is an inhibitor of β-secretase being evaluated for the treatment of Alzheimer's disease. The first-generation route relies on an amide coupling with a functionalized aniline, the preparation of which introduces synthetic inefficiencies. The s

A Next Generation Synthesis of BACE1 Inhibitor Verubecestat (MK-8931)

The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights of which include the application of a continuous processing step to outcompete fast proton transfer in a Mannich-type ketimine addition, a copper-cataly

A Single Quadrupole Compact Mass Spectrometer Enabling Early Stage Synthetic Optimization of Verubecestat (MK-8931)

A low-cost compact mass spectrometer was effectively utilized for identifying and tracking process impurities in the early stage development of a multistep synthetic protocol used to prepare the verubecestat drug substance. Process optimizations were infl

A NOVEL CRYSTALLINE FORM OF A BACE INHIBITOR, COMPOSITIONS, AND USE

The present invention provides a novel crystalline form of verubecestat (Crystalline Form II of Verubecestat) and pharmaceutically acceptable compositions thereof, each of which may be useful in treating, preventing, ameliorating, and/or delaying the onse

PROCESSES FOR THE PREPARATION OF A BACE INHIBITOR

This invention provides an improved processes for the preparation of verubecestat (Compound of Formula (I)), a potent inhibitor of BACE-1 and BACE-2.

PROCESSES FOR THE PREPARATION OF A BACE INHIBITOR

This invention provides processes for the preparation of verubecestat (Compound of Formula (I)), a potent inhibitor of BACE-1 and BACE-2. In addition, the invention provides certain synthetic intermediates which are useful, among other things, for the preparation of the Compound of Formula (I).