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Early development of small molecule neuroprotectants.

小分子神经保护剂的早期开发。

基本信息

批准号：
9977268
负责人：
Thomas D Bannister
金额：
$ 76.71万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977268
关键词：
ADP ribosylation Affinity Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Axotomy Behavioral Symptoms Binding Proteins Bioavailable Biological Biological Assay Biological Availability Biological Markers Brain Brain Ischemia Cell Death Cell Survival Cells Cellular Assay Chemicals Clinical Clinical Trials Consumption Cytochrome P450 Deposition Development Disease Drug Kinetics Evaluation Exhibits Exposure to Family Half-Life In Vitro Injections Injury Investigation Investigational Drugs KDR gene Knowledge Lead Link Liver Microsomes Metabolic Modeling Molecular Motor Multiple Sclerosis Mus Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurologic Neuronal Injury Neurons Neuroprotective Agents Oral Oxidative Stress Parkinson Disease Pathogenicity Pathway interactions Penetration Pharmaceutical Chemistry Pharmacology Phosphotransferases Plasma Plasma Proteins PrP Prevention Prion Diseases Property Proteins Proteomics Recovery Reperfusion Injury Rodent Model Safety Series Spices Structure-Activity Relationship Study Subject Testing Therapeutic Time Toxic effect Wallerian Degeneration analog base blood-brain barrier penetration cheminformatics design drug metabolism effective therapy excitotoxicity high throughput screening improved in vivo inhibitor/antagonist knock-down lead optimization lead series misfolded protein motor function improvement motor neuron function motor symptom mouse model muscle strength nanomolar neuron loss neuropathology neuroprotection neurotoxicity new therapeutic target novel overexpression preclinical efficacy preservation prevent protein misfolding receptor restoration scaffold screening small molecule urinary

项目摘要

SUMMARY NAD depletion occurs after excitotoxic insults and oxidative stress and causes neuronal death in several rodent models of neurodegenerative conditions, including models for brain ischemia/reperfusion injury and Wallerian degeneration. We have recently discovered that NAD depletion is also the primary cause of neuronal death induced by exposure to a misfolded and toxic form of the amyloidogenic prion protein (TPrP). NAD replenishment reversed the fate of TPrP-injured neurons in culture and improved motor function in a mouse model of prion disease. Therefore, our study established NAD restoration as a new therapeutic target for protein misfolding neurodegenerative diseases, a family of diseases that includes Alzheimer's, Parkinson's, prion diseases and amyotrophic lateral sclerosis (ALS). We developed a high- throughput screening strategy to identify NAD-dependent neuroprotective small molecules in the misfolded protein toxicity paradigm and then conducted a screening campaign. We identified and selected four chemical series providing complete neuroprotection and preserving NAD levels with nanomolar potency. One compound was tested in a murine model of ALS and improved the mice's muscle strength and motor function. We will conduct molecular mode of action studies for each chemical series, in conjunction with potency and drug metabolism and pharmacokinetic (DMPK) studies, to guide selection of the top lead. Lead optimization will be done through iterative rounds of structure-activity relationship studies and subjecting analogs to a series of in vitro and in vivo assays for potency, selectivity and absence of undesired off-target effects, as well as favorable DMPK properties including brain penetration. This workplan will deliver a novel small molecule neuroprotectant poised for investigational new drug (IND)–enabling studies and ultimately for the treatment of neurological conditions linked to a deficit in NAD.

总结