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Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)–A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer’s Disease

Journal Article · · Journal of Medicinal Chemistry
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  1. MRL, Merck & Co. Inc., Kenilworth, NJ (United States)
  2. MRL, Merck & Co. Inc., Kenilworth, NJ (United States); Tandem Laboratories, Ridgefield, CT (United States)
  3. MRL, Merck & Co. Inc., Kenilworth, NJ (United States); Charles River Labs, Boston, MA (United States)
  4. Albany Molecular Research Inc., Albany, NY (United States)
  5. MRL, Merck & Co. Inc., Kenilworth, NJ (United States); Big Boost Marketing, Hoboken, NJ (United States)
  6. MRL, Merck & Co. Inc., Kenilworth, NJ (United States); Metrohm, NJ (United States)
  7. Albany Molecular Research Inc., Albany, NY (United States); Momentive Performance Materials, Waterford, NY (United States)
  8. MRL, Merck & Co. Inc., Kenilworth, NJ (United States); Gilead Sciences, Foster City, CA (United States)
  9. MRL, Merck & Co. Inc., Kenilworth, NJ (United States); Tetranov International, Inc., New Brunswick, NJ (United States)
  10. MRL, Merck & Co. Inc., Kenilworth, NJ (United States); MedChem Discovery Consulting, Teaneck, NJ (United States)
+ Show Author Affiliations

Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer’s disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1404978
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 23 Vol. 59; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (19)

Pharmaceutical and medicinal significance of sulfur (SVI)-Containing motifs for drug discovery: A critical review journal January 2019
Safety, Tolerability, and Pharmacokinetics of the β‐Site Amyloid Precursor Protein‐Cleaving Enzyme 1 Inhibitor Verubecestat ( MK ‐8931) in Healthy Elderly Male and Female Subjects journal June 2019
Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment journal May 2018
Drug Development for Alzheimer’s Disease: Microglia Induced Neuroinflammation as a Target? journal January 2019
BACE-1 and γ-Secretase as Therapeutic Targets for Alzheimer’s Disease journal March 2019
Computer-Aided Multi-Target Management of Emergent Alzheimer’s Disease journal April 2018
Trifluoromethyl Dihydrothiazine‐Based β‐Secretase (BACE1) Inhibitors with Robust Central β‐Amyloid Reduction and Minimal Covalent Binding Burden journal October 2019
A Close Look at BACE1 Inhibitors for Alzheimer’s Disease Treatment journal March 2019
Stereodivergent Mannich reaction of bis(trimethylsilyl)ketene acetals with N-tert-butanesulfinyl imines by Lewis acid or Lewis base activation, a one-pot protocol to obtain chiral β-amino acids journal January 2017
β-secretase inhibitors for Alzheimer’s disease: identification using pharmacoinformatics journal February 2018
Investigation of intermolecular interactions and stability of verubecestat in the active site of BACE1: Development of first model from QM/MM-based charge density and MD analysis journal November 2018
Drug development for Alzheimer’s disease: review journal June 2018
Lessons that can be learnt from the failure of verubecestat in Alzheimer’s disease journal August 2019
A short perspective on the long road to effective treatments for Alzheimer's disease journal March 2019
Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer’s disease journal August 2019
A Novel Cell-based β-secretase Enzymatic Assay for Alzheimer’s Disease journal February 2019
β-secretase inhibitors for Alzheimer’s disease: identification using pharmacoinformatics text January 2018
β-secretase inhibitors for Alzheimer’s disease: identification using pharmacoinformatics text January 2018
Investigation of intermolecular interactions and stability of verubecestat in the active site of BACE1: Development of first model from QM/MM-based charge density and MD analysis text January 2018

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