Developing a novel treatment of cocaine use disorder using an IND dual inhibitor of Cav3 channel and soluble epoxide hydrolase

使用 Cav3 通道和可溶性环氧化物水解酶的 IND 双重抑制剂开发可卡因使用障碍的新型治疗方法

• 批准号: 10786151
• 负责人: Xinmin Simon Xie
• 金额: $ 31.95万
• 依托单位: AFASCI, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10786151
• 关键词: Action Potentials; American; Analgesics; Animal Model; Animals; Anti-Inflammatory Agents; Behavior; Behavioral; Binding; Biological; Biological Assay; Biological Availability; Brain; Canis familiaris; Cardiac; Cardiac Myocytes; Cardiotoxicity; Clinical Trials; Cocaine; Cocaine use disorder; Cocaine withdrawal; Collaborations; Data; Databases; Depressed mood; Dose Limiting; Drug Design; Drug Interactions; Drug Kinetics; Drug Targeting; Electrocardiogram; Electrophysiology (science); Epoxide hydrolase; Fos-Related Antigens; Future; Genetic; Goals; Grant; Habenula; Half-Life; Home; Human; In Vitro; Intake; Intravenous; Intravenous infusion procedures; Investigational Drugs; Investigational New Drug Application; Ion Channel; Knockout Mice; Lateral; Lead; Legal patent; Ligand Binding; Locomotion; Measures; Methods; Mibefradil; Mus; Neurons; Nose; Oral; Overdose; Patients; Penetration; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Phenotype; Plasma; Play; Polypharmacy; Rattus; Relapse; Reporting; Research; Rewards; Role; Safety; Schedule; Self Administration; Series; Slice; Small Business Innovation Research Grant; Spinal Ganglia; Substance Use Disorder; Synapses; Testing; Thalamic structure; Therapeutic; Toxic effect; Training; Universities; Ventral Tegmental Area; addiction; aged; animal efficacy; capsule; clinical development; cocaine reward; cocaine seeking; cocaine self-administration; cocaine use; drug candidate; effective therapy; evidence base; experience; feasibility testing; genotoxicity; healthy volunteer; improved; inhibitor; innovation; lead optimization; manufacture; medical schools; medication nonadherence; neural; neuroinflammation; neuronal excitability; neurotransmission; new chemical entity; novel; painful neuropathy; patch clamp; pharmacokinetics and pharmacodynamics; phase I trial; pill; pre-clinical; psychostimulant; response; screening; sex; side effect; single molecule; small molecule; stability testing; stimulant use disorder; success; therapeutic target

7. PROJECT SUMMARY Our SBIR Phase I proposal focuses on preclinical proof of concept studies on our IND AFA-281 for treatment cocaine use disorder (CUD). AFA-281 is a new chemical entity discovered by AfaSci that inhibits both the T-type Cav3 channels and soluble epoxide hydrolase (sEH). T-type channels consist of Cav3.1, 3.2, and 3.3 subunits. Cocaine activates ion channels, including T-channels in the brain to increase neuronal excitability and alter synaptic neurotransmission. Mibefradil, an old T-channel inhibitor blocks cocaine-induced GABAergic abnormalities and hyperlocomotion in mice. Studies in Cav3.1 knockout mice revealed T-type channels play a major role in sustaining ventral tegmental area neuronal excitability, and Cav3.2-deficient mice display reduced psychostimulant sensitivity. Hence, two Cav3 subunits are biologically validated as CUD drug targets. Recent studies suggest an involvement of neuroinflammation in addiction. Single sEH inhibitors or sEH genetic deletion show a reduction in neuroinflammation. Although sEH involvement in CUD is unknown, we hypothesize our dual inhibitor of Cav3/sEH could suppress cocaine-induced hyperexcitability and neuroinflammation, and thereby be an effective treatment for CUD. The goal of this project is to test this feasibility. This project’s innovation lies in AfaSci’s discovery of a series of patented dual modulators of Cav3 channels and sEH with a favorable druggable profile. AfaSci completed lead identification through rational drug design, iterative screenings using patch-clamp recordings and enzymatic assays. Lead optimization was conducted through 81 off-drug target selectivity screening and demonstrated no cardiac safety concerns using human cardiomyocytes in vitro. Based on pharmacokinetic and pharmacodynamic (PK/PD) studies, AFA-281 has shown an excellent oral bioavailability (70% in rats and 92% in dogs), acceptable t1/2 (2.5-4.3 h), CNS penetration, broad analgesic effects and good safety margins. Upon completion of the IND-enabling studies, AFA-281’s IND application was recently accepted by the FDA for a primary indication in neuropathic pain. In Preliminary Studies, we have shown cocaine-enhanced neural excitability was blocked by AFA-281 in rat thalamocortical slices. Rat cocaine-seeking behavior indicated by self-administration (SA) of intravenous (IV) infusion of cocaine solution was suppressed by AFA-281, and cocaine-elicited hyperlocomotion in rats and mice were restored to control levels by AFA-281. Our Specific Aim 1 in this project is to rigorously investigate AFA-281’s effects on rat intentional drug seeking via SA of IV infusion of cocaine in acquisition training and compulsive reward seeking under progress ratio schedule and on reinstatement in relapse. Our Specific Aim 2 is to investigate PK/PD of AFA-281 for suppressing cocaine seeking behavior and cocaine-induced hyperlocomotion in rats. Success in SBIR Phase I project will demonstrate proof of concept, leading to clinical development of AFA-281 for a secondary indication in CUD with an SBIR Phase II project and/or with third party support. Ultimately, AFA-281 as a safe, effective, and accessible medication will mitigate CUD.

7. 项目总结