om99-2 and Alzheimer-Disease

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

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Antiviral Agents; Aspartic Acid Endopeptidases; Biological Products; Darunavir; Drug Design; Drug Discovery; Drug Resistance, Viral; Enzyme Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Molecular Mimicry; Molecular Structure; Peptides; Structure-Activity Relationship; Sulfonamides

The exact cause of Alzheimer's disease is still unknown; despite the dramatic progress in understanding. Most gene mutations associated with Alzheimer's disease point to the amyloid precursor protein and amyloid beta. The alpha-, beta- and gamma-secretases are the three executioners of amyloid precursor protein processing. Significant progress has been made in the selective inhibition of these proteases, regardless of the availability of structural information. Several peptidic and non-peptidic leads were identified and first drug candidates are in clinical trials. Cholesterol lowering drugs and metal chelators are also in advanced clinical stages as disease modifiers. Successful trials demand either large cohorts or reliable markers for Alzheimer's disease. Therefore, several radiomarkers are under investigation to support such clinical trials.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Endopeptidases; Enzyme Inhibitors; Humans; Models, Molecular; Molecular Structure; Neuroprotective Agents; Oligopeptides; Positron-Emission Tomography; Radiopharmaceuticals

As beta-secretase, memapsin 2 cleaves amyloid-beta precursor protein, which leads ultimately to the onset of Alzheimer's disease. As such, memapsin 2 is an excellent target of inhibitor drugs for the treatment of this disease. Here we describe the tools for memapsin 2 inhibitor design that have been developed and results from the structure-based inhibitor design. Strategy for the design of memapsin 2 inhibitors with pharmaceutical potential is also discussed.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Crystallography, X-Ray; Drug Design; Endopeptidases; Humans; Oligopeptides; Protease Inhibitors

Novel 4-oxobenzo[d]1,2,3-triazin derivatives bearing pyridinium moiety 6a-q were synthesized and screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Most of the synthesized compounds showed good inhibitory activity against AChE. Among the synthesized compounds, the compound 6j exhibited the highest AChE inhibitory activity. It should be noted that these compounds displayed low anti-BuChE activity with the exception of the compound 6i, as it exhibited BuChE inhibitory activity more than donepezil. The kinetic study of the compound 6j revealed that this compound inhibited AChE in a mixed-type inhibition mode. This finding was also confirmed by the docking study. The latter study demonstrated that the compound 6j interacted with both the catalytic site and peripheral anionic site of the AChE active site. The compound 6j was also observed to have significant neuroprotective activity against H

Topics: Alzheimer Disease; Humans; Neuroprotective Agents; Pyridines

Alzheimer's disease (AD) is a neurodegenerative disorder known for the presence of amyloid beta plaques resulting from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. We developed and synthesized, through click reactions, a new family of iminochromene carboxamides containing different aminomethylene triazole. The BACE1 inhibition, neuroprotective capacity and metal chelation of these derivatives make them ideal candidates against AD. Most of the synthesized compounds were shown to have potent BACE1 inhibitory activity in a FRET assay, with an IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Benzopyrans; Cell Proliferation; Chelating Agents; Dose-Response Relationship, Drug; Humans; Molecular Structure; Neuroprotective Agents; PC12 Cells; Rats; Structure-Activity Relationship; Triazoles

A novel series of acridine-chromenone and quinoline-chromenone hybrids were designed, synthesized, and evaluated as anti-Alzheimer's agents. All synthesized compounds were evaluated as cholinesterases (ChEs) inhibitors and among them, 7-(4-(6-chloro-2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)phenoxy)-4-methyl-2H-chromen-2-one (8e) exhibited the most potent anti-acetylcholinesterase (AChE) inhibitory activity (IC50=16.17μM) comparing with rivastigmine (IC50=11.07μM) as the reference drug. Also, compound 8e was assessed for its β-secretase (BACE1) inhibitory and neuroprotective activities which demonstrated satisfactory results. It should be noted that both kinetic study on the inhibition of AChE and molecular modeling revealed that compound 8e interacted simultaneously with both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE.

Topics: Acridines; Alzheimer Disease; Animals; Cholinesterase Inhibitors; Cholinesterases; Chromones; Dose-Response Relationship, Drug; Drug Design; Humans; Models, Molecular; Molecular Structure; Neuroprotective Agents; PC12 Cells; Quinolines; Rats; Structure-Activity Relationship

Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD). AD is characterized by toxic β-amyloid (Aβ) peptides produced by β- and γ-secretase-mediated cleavage of the amyloid precursor protein (APP). β-secretase inhibitors reduce Aβ levels, but mechanism-based side effects arise because they also inhibit β-cleavage of non-amyloid substrates like Neuregulin. We report that β-secretase has a higher affinity for Neuregulin than it does for APP. Kinetic studies demonstrate that the affinities and catalytic efficiencies of β-secretase are higher toward non-amyloid substrates than toward APP. We show that non-amyloid substrates are processed by β-secretase in an endocytosis-independent manner. Exploiting this compartmentalization of substrates, we specifically target the endosomal β-secretase by an endosomally targeted β-secretase inhibitor, which blocked cleavage of APP but not non-amyloid substrates in many cell systems, including induced pluripotent stem cell (iPSC)-derived neurons. β-secretase inhibitors can be designed to specifically inhibit the Alzheimer process, enhancing their potential as AD therapeutics without undesired side effects.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cells, Cultured; Endocytosis; Endosomes; Golgi Apparatus; Humans; Induced Pluripotent Stem Cells; Kinetics; Mice; Molecular Dynamics Simulation; Neuregulin-1; Oligopeptides; Protein Processing, Post-Translational; Protein Transport; Proteolysis; Substrate Specificity

Alzheimer's disease is a grave social problem in an aging population. A major problem is the passage of drugs through the blood-brain barrier. This work tests the hypothesis that the conjugation of peptidomimetic β-secretase inhibitors with a fragment of amyloid-β peptide facilitates entrance into the central nervous system. HVR-3 (compound 4), one of the conjugation products, was found to be as potent as OM00-3, a known peptidomimetic inhibitor, 4-fold more selective toward β-secretase 1 in relation to β-secretase 2 and 3-fold more resistant to in vitro metabolization in human serum. Its intravenous administration to mice and Wistar rats generated an active metabolite recovered from the rodent's brains.

Topics: Acylation; Alzheimer Disease; Amino Acid Sequence; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Brain; Caco-2 Cells; Cell Survival; Drug Design; Female; Humans; Male; Mice; Molecular Sequence Data; Peptide Fragments; Peptidomimetics; Protease Inhibitors; Rats; Structure-Activity Relationship

The inhibition of β secretase (BACE1) is potentially important approach to treatment of Alzheimer disease (AD). A novel series of 4-bromophenyl piperazine derivatives coupled to the phenylimino-2H-chromen-3-carboxamide scaffold were investigated as BACE1 inhibitors in this study. Docking study suggested that the phenyl-imino group of the scaffold establishes favorable π-π stacking interaction with side chain of Phe108 of flap pocket. Some of the docking proposed derivatives were synthesized and evaluated for BACE1 inhibitory activity using a FRET-based assay. High BACE1 inhibitory activities were observed from derivatives containing fused heteroaromtic groups attached through the aliphatic linkage to the N4-piperazine moiety, which may be attributed to the engagement of effective interactions with S1-S'1 sub-pocket residues. Of the most potent compounds, 9e displayed an IC50 value for BACE1 of 98 nM. Some of these derivatives demonstrated good inhibitory activity on Aβ production in N2a-APPswe cells at 5 and 10 μM. These compounds might be considered as promising BACE1 inhibitory agents that could lower Aβ production in AD.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Benzopyrans; Cell Line, Tumor; Humans; Mice; Molecular Docking Simulation; Neuroblastoma

Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived β-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K(i)=13 nM) and cellular (IC(50)=21 nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound β-secretase. The model suggested possible interactions in the active site.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Catalytic Domain; Cell Line, Tumor; Crystallography, X-Ray; Drug Design; Enzyme Inhibitors; Humans; Models, Molecular; Pyrazoles; Quinazolines; Structure-Activity Relationship; Thiazoles

The synthesis, evaluation, and structure-activity relationships of a set of related constrained diaminopropane inhibitors of BACE-1 are described. The full in vivo profile of an optimized inhibitor in both normal and P-gp deficient mice is compared with data generated in normal rats.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; ATP Binding Cassette Transporter, Subfamily B, Member 1; Crystallography, X-Ray; Diamines; Enzyme Inhibitors; HEK293 Cells; Humans; Mice; Mice, Knockout; Models, Molecular; Rats; Structure-Activity Relationship

A novel series of quinoxaline derivatives, as Multi-Target-Directed Ligands (MTDLs) for AD treatment, were designed by lending the core structural elements required for H(3)R antagonists and hybridizing BACE 1 inhibitor 1 with AChE inhibitor BYYT-25. A virtual database consisting of quinoxaline derivatives was first screened on a pharmacophore model of BACE 1 inhibitors, and then filtered by a molecular docking model of AChE. Seventeen quinoxaline derivatives with high score values were picked out, synthesized and evaluated for their biological activities. Compound 11a, the most effective MTDL, showed the potent activity to H(3)R/AChE/BACE 1 (H(3)R antagonism, IC(50)=280.0 ± 98.0 nM; H(3)R inverse agonism, IC(50)=189.3 ± 95.7 nM; AChE, IC(50)=483 ± 5 nM; BACE 1, 46.64±2.55% inhibitory rate at 20 μM) and high selectivity over H(1)R/H(2)R/H(4)R. Furthermore, the protein binding patterns between 11a and AChE/BACE 1 showed that it makes several essential interactions with the enzymes.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Cholinesterase Inhibitors; Histamine H3 Antagonists; Humans; Kinetics; Ligands; Models, Molecular; Quinoxalines; Receptors, Histamine H3; Structure-Activity Relationship

Dual-target-directed 1,3-diphenylurea derivatives were designed by hybridizing BACE 1 inhibitor 1 with metal chelator LR-90. A database consisted of 1,3-diphenylurea derivatives was built and screened by the pharmacophore model (Hypo 1) of BACE 1 inhibitor. Based on the predicted results, 11 compounds (6a-d, 9a-g) with favorable Fitvalues were selected, synthesized and evaluated for their BACE 1 inhibitory activities, which showed that the predicted results were in good agreement with the experimental values. Besides, the synthesized compounds also displayed the ability to chelate metal ions. The most effective BACE 1 inhibitor 9f (27.85+/-2.46 micromol/L) was selected for further receptor-binding studies, the result of which indicated that an essential hydrogen bonds was formed between the urea group of 9f and the catalytic aspartate Asp228.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Binding Sites; Butyrates; Carbanilides; Chelating Agents; Computer Simulation; Humans; Metals; Models, Molecular; Phenylurea Compounds

To explore novel effective drugs for the treatment of Alzheimer's disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and beta-secretase (BACE-1) were designed based on the multi-target-directed ligands strategy. Among them, inhibitor 28 exhibited good dual potency in enzyme inhibitory potency assay (BACE-1: IC(50)=0.567 microM; AChE: IC(50)=1.83 microM), and also showed excellent inhibitory effects on Abeta production of APP transfected HEK293 cells (IC(50)=98.7 nM) and mild protective effect against hydrogen peroxide (H(2)O(2))-induced PC12 cell injury. Encouragingly, intracerebroventricular injection of 28 into amyloid precursor protein (APP) transgenic mice caused a 29% reduction of Abeta(1-40) production. Therefore, 28 was demonstrated as a good lead compound for the further study and more importantly, the strategy of AChE and BACE-1 dual inhibitors might be a promising direction for developing novel drugs for AD patients.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Cell Line; Cholinesterase Inhibitors; Drug Design; Humans; Mice; Mice, Knockout; Mice, Transgenic; Models, Molecular; Protease Inhibitors; Rats

Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic beta-secretase inhibitors incorporating hydroxyethylamine isosteres are described. We have identified inhibitor 24 which has shown exceedingly potent activity in memapsin 2 enzyme inhibitory (K(i) 1.8 nM) and cellular (IC(50)=1 nM in Chinese hamster ovary cells) assays. Inhibitor 24 has also shown very impressive in vivo properties (up to 65% reduction of plasma A beta) in transgenic mice. The X-ray structure of protein-ligand complex of memapsin 2 revealed critical interactions in the memapsin 2 active site.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid; Aspartic Acid Endopeptidases; Cricetinae; Cricetulus; Crystallography, X-Ray; Dipeptides; Drug Design; Female; Humans; Mice; Mice, Transgenic; Models, Molecular; Molecular Structure; Structure-Activity Relationship; Sulfonamides

The aspartic protease beta-secretase (BACE) cleaves the amyloid precursor protein into a 42 residue beta-peptide, which is the principal biochemical marker of Alzheimer's disease. Multiple explicit-water molecular dynamics simulations of the apo and inhibitor bound structures of BACE indicate that both open- and closed-flap conformations are accessible at room temperature and should be taken into account for inhibitor design. Correlated motion is observed within each of the two lobes of BACE, as well as for the interfacial region. A self-inhibited conformation with the side chain of Tyr71 occupying the S(1) pocket is present in some of the unbound simulations. The reversible loss of the side chain hydrogen bond between the catalytic Asp32 and Ser35, due to the concomitant reorientation of the Ser35 hydroxyl group and a water molecule conserved in pepsin-like enzymes, provides further evidence for the suggestion that Ser35 assists in proton acceptance and release by Asp32 during catalysis.

Topics: Alzheimer Disease; Amino Acid Sequence; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Asparagine; Aspartic Acid Endopeptidases; Binding Sites; Catalysis; Computer Simulation; Crystallography, X-Ray; Endopeptidases; Enzyme Inhibitors; Humans; Hydrogen Bonding; Kinetics; Models, Molecular; Molecular Sequence Data; Oligopeptides; Protein Conformation; Protein Structure, Secondary; Protons; Serine; Substrate Specificity; Temperature; Tyrosine; Water

Utilizing structure-based techniques and solid-phase synthesis, statine-based tetrapeptide BACE inhibitors were designed and synthesized using a heptapeptide BACE transition-state mimetic, 1, as the starting point. Structure-activity relationship studies at the P(3), P(2), and P(2)' positions as well as the N-terminal capping group on scaffold 5 led to the discovery of potent inhibitors 27, 32, and 34 (IC(50) <100 nM). In addition, computational analysis and the X-ray structure of BACE-inhibitor 38 are discussed.

Topics: Alzheimer Disease; Amino Acid Sequence; Amino Acids; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Drug Design; Endopeptidases; Enzyme Inhibitors; Humans; Kinetics; Models, Molecular; Structure-Activity Relationship