ly2811376 and Alzheimer-Disease

β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors offer the potential of disease-modifying treatment for Alzheimer's disease (AD). Since 2014, major breakthroughs have appeared in the field of BACE1 inhibitors. This review provides an overview of amidine-based BACE1 inhibitors between 2014 and 2018. Herein are summarized i) the structure-activity relationship, ii) the physiological results and iii) the potential risks from a lack of selectivity. This review also summarizes clinical scope, results and outlook of the compounds that have been or are currently under development in clinical trials.

Topics: Alzheimer Disease; Amidines; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Heterocyclic Compounds; Humans; Molecular Structure; Protease Inhibitors; Structure-Activity Relationship

The amyloid hypothesis has long been the central dogma in drug discovery for Alzheimer's disease (AD), leading to many small-molecule and biological drug candidates. One major target has been the β-site amyloid-precursor-protein-cleaving enzyme 1 (BACE-1), with many big pharma companies expending great resources in the search for BACE-1 inhibitors. The lack of efficacy of verubecestat in mild-to-moderate AD raises important questions about the timing of intervention with BACE-1 inhibitors, and anti-amyloid therapies in general, in AD treatment. It also suggests new possibilities for discovering BACE-1-targeted compounds with more complex mechanisms of actions and improved efficacy. Herein, we review the major advances in BACE-1 drug discovery, from single-target small molecule inhibitors to multitarget compounds. We discuss these compounds as innovative tools for better understanding the complexity of AD and for identifying efficacious drug candidates to treat this devastating disease.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Glycogen Synthase Kinase 3 beta; Humans; Molecular Targeted Therapy; Protease Inhibitors

Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors hold great potential as disease modifying anti-Alzheimer's drugs. This digest provides an overview of the amidine containing class of BACE1 inhibitors, of which multiple examples are now progressing through clinical trials. The various structural modifications highlight the struggle to combine potency with the optimal properties for a brain penetrant BACE1 inhibitor, and illustrate the crowded competitive landscape. This overview concludes with a summary of potential issues including substrate and target selectivity and a synopsis of the status of the current and past clinical assets.

Topics: Alzheimer Disease; Amidines; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Brain; Drug Discovery; Humans; Models, Molecular

The development of new therapeutics for the treatment of neurodegenerative pathophysiologies currently stands at a crossroads. This presents an opportunity to transition future drug discovery efforts to target disease modification, an area in which much still remains unknown. In this Perspective we examine recent progress in the areas of neurodegenerative drug discovery, focusing on some of the most common targets and mechanisms: N-methyl-d-aspartic acid (NMDA) receptors, voltage gated calcium channels (VGCCs), neuronal nitric oxide synthase (nNOS), oxidative stress from reactive oxygen species, and protein aggregation. These represent the key players identified in neurodegeneration and are part of a complex, intertwined signaling cascade. The synergistic delivery of two or more compounds directed against these targets, along with the design of small molecules with multiple modes of action, should be explored in pursuit of more effective clinical treatments for neurodegenerative diseases.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Antioxidants; Calcium Channels; Drug Combinations; Drug Design; Humans; Huntington Disease; Neurodegenerative Diseases; Nitric Oxide Synthase Type I; Oxidative Stress; Parkinson Disease; Protein Folding; Protein Structure, Quaternary; Proteostasis Deficiencies; Receptors, N-Methyl-D-Aspartate

The amyloid hypothesis asserts that excess production or reduced clearance of the amyloid-β (Aβ) peptides in the brain initiates a sequence of events that ultimately lead to Alzheimer's disease and dementia. The Aβ hypothesis has identified BACE1 as a therapeutic target to treat Alzheimer's and led to medicinal chemistry efforts to design its inhibitors both in the pharmaceutical industry and in academia. This review summarizes two distinct categories of inhibitors designed based on conformational states of "closed" and "open" forms of the enzyme. In each category the inhibitors are classified based on the core catalytic interaction group or the aspartyl binding motif (ABM). This review covers the description of inhibitors in each ABM class with X-ray crystal structures of key compounds, their binding modes, related structure-activity data highlighting potency advances, and additional properties such as selectivity profile, P-gp efflux, pharmacokinetic, and pharmacodynamic data.

Topics: Alzheimer Disease; Amino Acid Sequence; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Biocatalysis; Blood-Brain Barrier; Cell Membrane Permeability; Clinical Trials as Topic; Humans; Isoenzymes; Models, Molecular; Molecular Sequence Data; Protein Binding; Protein Conformation; Structure-Activity Relationship

Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer's disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Crystallography, X-Ray; Cyclopropanes; Dose-Response Relationship, Drug; Humans; Ligands; Models, Molecular; Molecular Conformation; Protease Inhibitors; Structure-Activity Relationship

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Humans; Structure-Activity Relationship

This Letter describes the synthesis and structure-activity relationships of a series of furo[2,3-d][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine 2e bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3-d]thiazine can serve as a viable bioisostere of the known furo[3,4-d]thiazine.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Catalytic Domain; Enzyme Inhibitors; Furans; Humans; Models, Molecular; Protein Binding; Thiazines

The identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid β (Aβ) levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of Aβ-derived plaques. Most importantly, evaluation of 36 in a 2-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors.

Topics: Alzheimer Disease; Amidines; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Brain; Dogs; Drug Design; Enzyme Inhibitors; Humans; Male; Mice; Models, Molecular; Plaque, Amyloid; Rats; Rats, Wistar; Sulfhydryl Compounds