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New piperazines effecting Abeta oligomer displacement from neuronal receptors

新哌嗪影响神经元受体中 Abeta 寡聚物的置换

基本信息

批准号：
9047381
负责人：
NICHOLAS John IZZO
金额：
$ 22.4万
依托单位：
COGNITION THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-15 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9047381
关键词：
Acute Advanced Development Affinity Alzheimer&apos s Disease Amyloid beta-Protein Animal Model Base of the Brain Binding Sites Bioavailable Biological Assay Biological Availability Bolus Infusion Brain Cells Clinic Clinical Clinical Trials Cognition Competitive Binding Development Disease Disease Progression Dose Drug Industry Drug Kinetics Event Feasibility Studies Feedback Functional disorder Funding Future Goals Grant Hepatocyte Human Impaired cognition In Vitro Lead Ligands Measurement Measures Mediating Membrane Protein Traffic Memory Memory impairment Metabolic Mission Modification Mus Neurons Oral Oral Administration Parents Pathology Patients Permeability Pharmaceutical Preparations Phase Piperazines Plasma Preparation Process Production Property Proteins Radio Research Risk Schedule Series Signal Transduction Structure Symptoms Synapses System Testing Therapeutic Transgenic Animals Variant Work abeta oligomer absorption analog base design drug development follow-up improved in vivo iterative design lead series meetings member mild cognitive impairment mouse model novel phase 1 study pre-clinical preclinical study prevent public health relevance receptor receptor binding risk mitigation scaffold small molecule small molecule therapeutics trafficking

项目摘要

DESCRIPTION (provided by applicant): Cognition Therapeutics Inc.'s mission is to develop effective therapeutics for Alzheimer's disease. Recent scientific discoveries have identified oligomers of the brain protein Abeta 42 as toxic culprits in the disease process. Cognition has discovered therapeutic molecules that displace Abeta oligomers from neurons and block the downstream pathological signaling that inhibits memory formation. These therapeutic small molecules should prevent further oligomer-induced damage, and unmask existing memory capacity as synapses recover. These molecules act through modulating a newly identified receptor target. They are hypothesized to be disease-modifying treatments that would be effective throughout the course of the disease, and significantly impact the lives of millions of Alzheimer's patients. Pharmaceutical industry efforts targeted specifically at Abeta oligomer blockade are currently limited. Cognition Therapeutics is one of the only companies uniquely focused on discovery of small molecule oligomer-displacing therapeutics. We have discovered a CNS drug-like lead series of oligomer-displacing compounds, the CT0109 Series. Analogs in this series displace oligomers from neurons and completely block Abeta oligomer-induced membrane trafficking changes and synapse loss. Members of this series are highly brain-penetrant and completely block oligomer-induced memory deficits in Alzheimer's disease mouse models. Further preclinical development of these analogs is progressing. However, new structural variants with different physicochemical profiles will provide a measure of risk mitigation in the event that our current candidates fail to advance through the clinic due to unforeseen issues. We propose to explore a new piperazine variant of the CT0109 series. This new variant would possess physiochemical properties previously unexplored in the current series. This proposal will allow us to expand our portfolio of Abeta oligomer-displacing compounds and establish the feasibility of these variants to be optimized with the goal of obtaining orally efficacious candidates for further development as therapeutics for AD.