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Title: 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)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1404978
Journal Information:
Journal of Medicinal Chemistry, Vol. 59, Issue 23; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 107 works
Citation information provided by
Web of Science

References (57)

Dementia: a global health priority - highlights from an ADI and World Health Organization report journal September 2012
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide journal February 2007
The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics journal July 2002
The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics journal August 2011
The Genetics of Alzheimer Disease journal July 2012
Alzheimer's disease: strategies for disease modification journal May 2010
A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline journal July 2012
BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics journal June 2001
Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects journal April 2014
Beta-Secretase Cleavage of Alzheimer's Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE journal October 1999
Purification and cloning of amyloid precursor protein β-secretase from human brain journal December 1999
Identification of a Novel Aspartic Protease (Asp 2) as β-Secretase journal December 1999
Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity journal December 1999
Human aspartic protease memapsin 2 cleaves the beta -secretase site of beta -amyloid precursor protein journal February 2000
The evolution of amidine-based brain penetrant BACE1 inhibitors journal May 2014
Structure-Based Design of β-Site APP Cleaving Enzyme 1 (BACE1) Inhibitors for the Treatment of Alzheimer’s Disease journal April 2013
Small-molecule BACE1 inhibitors: a patent literature review (2006 – 2011) journal April 2012
Control of Peripheral Nerve Myelination by the  -Secretase BACE1 journal October 2006
Bace1 modulates myelination in the central and peripheral nervous system journal November 2006
Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles journal June 2013
Partial Reduction of BACE1 Has Dramatic Effects on Alzheimer Plaque and Synaptic Pathology in APP Transgenic Mice journal September 2007
Application of Fragment-Based NMR Screening, X-ray Crystallography, Structure-Based Design, and Focused Chemical Library Design to Identify Novel μM Leads for the Development of nM BACE-1 (β-Site APP Cleaving Enzyme 1) Inhibitors journal December 2009
Discovery of Cyclic Acylguanidines as Highly Potent and Selective β-Site Amyloid Cleaving Enzyme (BACE) Inhibitors: Part I—Inhibitor Design and Validation journal December 2009
Inhibitors of BACE for treating Alzheimer's disease: a fragment-based drug discovery story journal June 2013
Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor journal April 2012
Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS Aβ Reduction journal July 2012
Design and Validation of Bicyclic Iminopyrimidinones As Beta Amyloid Cleaving Enzyme-1 (BACE1) Inhibitors: Conformational Constraint to Favor a Bioactive Conformation journal September 2012
Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates journal March 2016
Core Refinement toward Permeable β-Secretase (BACE-1) Inhibitors with Low hERG Activity journal May 2013
Fast Calculation of Molecular Polar Surface Area as a Sum of Fragment-Based Contributions and Its Application to the Prediction of Drug Transport Properties journal October 2000
Cathepsin D Deficiency Induces Lysosomal Storage with Ceroid Lipofuscin in Mouse CNS Neurons journal September 2000
Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis journal April 2006
Robust Central Reduction of Amyloid-  in Humans with an Orally Available, Non-Peptidic  -Secretase Inhibitor journal November 2011
Retinal Toxicity Induced by a Novel β-secretase Inhibitor in the Sprague-Dawley Rat journal October 2014
Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design journal February 2015
Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design. journal July 1993
Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure-Based Design and in Vivo Reduction of Amyloid β-Peptides journal March 2012
Kinesin spindle protein (KSP) inhibitors. Part V: Discovery of 2-propylamino-2,4-diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by β-fluorination to overcome cellular efflux by P-glycoprotein journal May 2007
Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists journal March 2013
Macrocyclic BACE-1 inhibitors acutely reduce Aβ in brain after po application journal January 2010
P1-231: Chronic BACE inhibition dramatically slows the rate of Aß accumulation and the development of amyloid plaques in young TgCRND8 mice journal July 2012
P1-232: Chronic BACE inhibition halts further age-related increases in brain Aß and amyloid plaques in aged TgCRND8 mice with established plaques journal July 2012
Torsion Angle Preferences in Druglike Chemical Space: A Comprehensive Guide journal February 2013
The BACE1 inhibitor verubecestat (MK-8931) reduces CNS  -amyloid in animal models and in Alzheimers disease patients journal November 2016
Crystal Structure of Human BACE2 in Complex with a Hydroxyethylamine Transition-state Inhibitor journal January 2006
Estimation of Blood-Brain Barrier Crossing of Drugs Using Molecular Size and Shape, and H-Bonding Descriptors journal January 1998
Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space journal January 2011
A Novel Model for Prediction of Human drug Clearance by Allometric Scaling journal June 2005
In Silico hERG Modeling: Challenges and Progress journal June 2009
Drug-Induced Prolongation of the QT Interval journal March 2004
BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells journal June 2013
Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice journal February 2016
Bace2 Is a β Cell-Enriched Protease that Regulates Pancreatic β Cell Function and Mass journal September 2011
Stereoselective Synthesis of β-Substituted β-Amino Sulfones and Sulfonamides via Addition of Sulfonyl Anions to Chiral N -Sulfinyl Imines journal February 2006
General One-Pot Method for the Preparation of N - tert -Butanesulfinylamine Diastereomer Mixtures as Standards for Stereoselectivity Determinations journal April 2009
Synthesis and properties of the sulfonyl analogs of 4(5)-aminoimidazole-5(4)-carboxamide, 4(5)-(formylamino)imidazole-5(4)-carboxamide, guanine, and xanthine journal May 1980
Synthesis of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer’s Disease journal November 2016

Cited By (19)

BACE-1 and γ-Secretase as Therapeutic Targets for Alzheimer’s Disease journal March 2019
β-secretase inhibitors for Alzheimer’s disease: identification using pharmacoinformatics journal February 2018
Drug development for Alzheimer’s disease: review journal June 2018
Trifluoromethyl Dihydrothiazine‐Based β‐Secretase (BACE1) Inhibitors with Robust Central β‐Amyloid Reduction and Minimal Covalent Binding Burden journal October 2019
Lessons that can be learnt from the failure of verubecestat in Alzheimer’s disease journal August 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 Close Look at BACE1 Inhibitors for Alzheimer’s Disease Treatment journal March 2019
A short perspective on the long road to effective treatments for Alzheimer's disease journal March 2019
A Novel Cell-based β-secretase Enzymatic Assay for Alzheimer’s Disease journal February 2019
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
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
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
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
β-secretase inhibitors for Alzheimer’s disease: identification using pharmacoinformatics text January 2018
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
Computer-Aided Multi-Target Management of Emergent Alzheimer’s Disease journal April 2018

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