Alzheimer's disease (AD) is an age-related neurodegenerative disease that has become a global epidemic with over 40 million people affected worldwide and a projected 115 million in 2050. It is the 6th leading cause of death in the United States. AD has a tremendous impact on health, society and the economy. Approved treatments at best partially ameliorate some symptoms. There is an urgent need for novel, disease-modifying treatments. AD is a complex disease with multiple players that may be targeted for therapeutic intervention. A core pathogenic mechanism is the cellular toxicity of Ab42 peptide oligomers with the cascade of activation and phosphorylation events that follow neuronal oligomeric Ab42 binding and internalization. These result, inter alia, in oxidative stress, mitochondrial dysfunction, synaptic dysfunction, abnormal Ca2+ signaling and excitotoxicity. The overarching goal of this project is to develop a drug targeting neurotoxic Ab42 signaling. In this phase 1 component of the project, we will demonstrate the feasibility of optimizing our candidate compound into a therapeutic lead. We will conduct several rounds of structure-activity relationship studies aimed at increasing the compound's potency, selectivity, metabolic and pharmacokinetic properties, including brain penetration. A series of in vitro/cell-based assays, DMPK studies and testing in a murine AD model will guide compound progression. The successful completion of phase 1 will deliver an optimized lead compound ready for development and IND-enabling studies in phase 2.
Public Health Relevance Statement: Alzheimer's disease has become a worldwide health challenge with over 40 million patients and the absence of disease-modifying therapy. In this project, we will demonstrate the feasibility to develop a candidate compound targeting neurotoxic signaling into a lead for Alzheimer's disease. This work will open up a new therapeutic approach for this condition in response to a huge unmet need.
Project Terms: Affect; Alzheimer's Disease; AD dementia; Alzheimer; Alzheimer Type Dementia; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's disease dementia; Alzheimers Dementia; Alzheimers disease; Primary Senile Degenerative Dementia; dementia of the Alzheimer type; primary degenerative dementia; senile dementia of the Alzheimer type; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Biologic Availability; Physiologic Availability; Blood Circulation; Bloodstream; Circulation; Brain; Brain Nervous System; Encephalon; Cause of Death; Cell Survival; Cell Viability; Cells; Cell Body; chemical synthesis; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Cytochrome P450; Cytochrome P-450; Cytochrome P-450 Enzyme System; Cytochrome P450 Family Gene; P450; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Enzymes; Enzyme Gene; Epidemic; Florida; Goals; Half-Life; Health; Human; Modern Man; Hydrogen Bonding; H-bond; In Vitro; Ion Channel; Ionic Channels; Membrane Channels; Lead; Pb element; heavy metal Pb; heavy metal lead; Membrane Proteins; Membrane Protein Gene; Membrane-Associated Proteins; Surface Proteins; Memory; Liver Microsomes; Mus; Mice; Mice Mammals; Murine; Persons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Neurons; Pathology; Patients; Peptides; Permeability; Pharmacokinetics; Drug Kinetics; Pharmacology; Protein Phosphorylation; Phosphorylation; Kinases; Phosphotransferase Gene; Transphosphorylases; Phosphotransferases; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma; Rodentia; Rodents Mammals; Rodent; Safety; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Signal Transduction; Societies; Specificity; chemical structure function; structure function relationship; Structure-Activity Relationship; Synaptic; synapse; Synapses; Testing; United States; Work; tau Proteins; MT-bound tau; microtubule bound tau; microtubule-bound tau; tau; tau factor; Ï Proteins; base; improved; Area; Surface; Penetration; Phase; Biochemical; Series; Evaluation; immunocytochemistry; Oxidative Stress; analog; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Intellectual Property; PSEN1; S182 protein; presenilin 1 protein; presenilin-1; Therapeutic; Metabolic; Exposure to; depressed; sadness; Depressed mood; Complex; Event; Oral; Isoforms; Protein Isoforms; Receptor Protein; receptor; Toxicities; Toxic effect; novel; G Protein-Complex Receptor; G Protein-Coupled Receptor Genes; GPCR; G-Protein-Coupled Receptors; drug metabolism; Cell surface; Position; Positioning Attribute; intervention therapy; Therapeutic Intervention; neuroblastoma cell; Property; response; High Throughput Assay; high throughput screening; Pathogenicity; Molecular Interaction; Binding; therapeutic testing; therapeutic evaluation; small molecule; Mediator; Mediator of Activation; Mediator of activation protein; Dose; Symptoms; Affinity; Degradative Pathway; Degradation Pathway; in vivo; Monitor; Development; developmental; Behavioral; excitotoxicity; neurotoxic; mitochondrial dysfunction; Alzheimer's disease model; AD model; alzheimer model; induced pluripotent stem cell; iPS; iPSC; iPSCs; inducible pluripotent stem cell; age related neurodegeneration; age-related neurodegenerative disease; age-related neurodegenerative disorder; novel therapeutic intervention; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; Biological Markers; bio-markers; biologic marker; biomarker; PrP; PrP Proteins; Prion Proteins; Drug Targeting; targeted treatment; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; Knock-in; knockin; clinical development; preclinical development; pre-clinical development; screening panel; novel lead compound; lead optimization; lead candidate; bioinformatics tool; bio-informatics tool; in silico; Alzheimer's disease patient; Alzheimer's patient; Alzheimer's disease brain; Alzheimer's brain
