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Alzheimer’s Disease II pp 27–85Cite as

The Design, Development, and Evaluation of BACE1 Inhibitors for the Treatment of Alzheimer’s Disease

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Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 24))

Abstract

Alzheimer’s disease (AD) is a very serious public health problem. Currently, there is no effective treatment for AD. Among the many biochemical targets for AD drug development, β-secretase (BACE1, memapsin 2) continues to be a promising drug discovery target for AD therapy. This proteolytic enzyme is a membrane-anchored aspartic acid protease that is responsible for the initial step of amyloid precursor protein (APP) cleavage, leading to the production of neurotoxic amyloid-β (Aβ) peptides in the brain. Since its identification and structural elucidation in 1999, extensive research efforts have led to the development of many promising classes of inhibitors against this protease. Structure-based design strategies led to the evolution of many small-molecule, peptidomimetic, and nonpeptide BACE1 inhibitors that have now overcome the key development challenges including selectivity and brain penetration. To date, 13 BACE1 drug candidates have been brought to clinical trials, and a number of them have advanced to phase II/III human trials. This chapter illustrates structure-based evolution of various classes of BACE inhibitors. Also, it provides a perspective on BACE1 inhibitor drugs for the treatment of AD patients.

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Abbreviations

Aβ:

Amyloid-β protein

AD:

Alzheimer’s Disease

ADAS:

Alzheimer’s Disease Assessment Scale

ADAS-Cog:

Alzheimer’s Disease Assessment Scale-Cognitive Subscale

ADCS:

Alzheimer’s Disease Cooperative Study

ADCS-ADL:

Alzheimer’s Disease Cooperative Study-Activities of Daily Living

ADCS-PACC:

Alzheimer’s Disease Cooperative Study-Preclinical Alzheimer’s Cognitive Composite

ADME:

Absorption distribution, metabolism, and excretion

APP:

Amyloid precursor protein

BACE1:

β-Site amyloid precursor protein-cleaving enzyme 1

BACE2:

β-Site amyloid precursor protein-cleaving enzyme 2

BBB:

Blood–brain barrier

CatD:

Cathepsin D

CCS-3D:

3-Domain Composite Cognition Score

CDR:

Clinical Dementia Rating Scale

CDR-SB:

Clinical Dementia Rating Sum of Boxes

CFI:

Cognitive Function Instrument

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

C-SSRS:

Columbia-Suicide Severity Rating Scale

ECG:

Electrocardiogram

FDA:

Food and Drug Administration

HIV:

Human immunodeficiency virus

HTS:

High-throughput screening

IC50 :

50% inhibitory concentration

K i :

Inhibitory constant

MMSE:

Mini Mental State Examination

MRI:

Magnetic resonance imaging

MWM:

Morris water maze

NMDA:

N-Methyl d-aspartate

NPI:

Neuropsychiatric Inventory

NTB:

Neuropsychological Test Battery

PET:

Positron emission tomography

Pgp:

P-glycoprotein

QT:

Q-wave to T-wave interval

sAPPα:

Soluble amyloid precursor protein α-fragment

sAPPβ:

Soluble amyloid precursor protein β-fragment

SAR:

Structure-activity relationship

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Acknowledgment

The authors’ work in the article was supported by the National Institutes of Health. We would also like to thank Ms. Anne Veitschegger and Mr. Luke Kassekert (both Purdue University) for their helpful discussions.

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Authors and Affiliations

  1. Department of Chemistry, Purdue University, West Lafayette, IN, USA

    Arun K. Ghosh, Emilio L. Cárdenas & Heather L. Osswald

  2. Department of Medicinal Chemistry, Purdue University, West Lafayette, IN, USA

    Arun K. Ghosh

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  1. Arun K. Ghosh
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  2. Emilio L. Cárdenas
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Correspondence to Arun K. Ghosh .

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  1. Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas, USA

    Michael S. Wolfe

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Ghosh, A.K., Cárdenas, E.L., Osswald, H.L. (2016). The Design, Development, and Evaluation of BACE1 Inhibitors for the Treatment of Alzheimer’s Disease. In: Wolfe, M. (eds) Alzheimer’s Disease II. Topics in Medicinal Chemistry, vol 24. Springer, Cham. https://doi.org/10.1007/7355_2016_16

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