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Peripherally restricted α2/δ-1 subunit ligands that modulate CaV channel gating as novel antiarrhythmic drugs

外周限制的α2/β-1亚基配体作为新型抗心律失常药物调节CaV通道门控

基本信息

批准号：
9406676
负责人：
Uwe Klein
金额：
$ 22.49万
依托单位：
NUMERATE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9406676
关键词：
Active Biological Transport Address Adverse effects Affinity American Amino Acid Transport System A Amino Acids Anti-Arrhythmia Agents Applications Grants Back Binding Bioavailable Biological Assay Blood - brain barrier anatomy Blood Circulation Caco-2 Cells Calcium Channel Cardiac Cardiovascular system Cause of Death Cells Chronic Classification Computer Simulation Dizziness Dose Drug Efflux Electrophysiology (science)Goals Health Heart Human In Vitro Knowledge Laboratory Research Ligands Mediating Memory Loss Modeling Mus Muscle Cells Oral Oryctolagus cuniculus Oxidative Stress P-Glycoprotein Performance Peripheral Pharmaceutical Preparations Pharmacotherapy Prevention Preventive Property Pump Rattus Regulation Risk Sedation procedure Series Site Small Business Innovation Research Grant Testing Therapeutic Ventricular Ventricular Fibrillation Ventricular Tachycardia Work Xenopus oocyte base design efflux pump in vivo intraperitoneal member novel novel therapeutics patch clamp predictive modeling prevent radioligand screening small molecule sudden cardiac death virtual voltage

项目摘要

Abstract Sudden Cardiac Death (SCD) caused by ventricular tachycardias and fibrillation (VT/VF) is a major world-wide health problem claiming the lives of some 300,000 Americans each year. Current antiarrhythmic drug (AAD) therapy to control VT/VF is largely empirical and poorly efficacious with considerable risk of proarrhythmic effects. There remains considerable unmet need for new, safe and effective AADs that specifically target the electrophysiological underpinnings of VT/VF without compromising cardiac function. Our goal is to discover and develop a small molecule antiarrhythmic drug that will address this need. Members of the Cardiovascular Research Laboratory at UCLA, Drs. Hrayr Karagueuzian and Riccardo Olcese, have recently advanced our understanding of the functional regulation of the voltage dependent calcium channel CaV1.2 by the α2δ-1 subunit, and how modulation of CaV1.2 gating can reduce VT/VF triggered by early afterdepolarizations (EADs). They have also demonstrated the effect of gabapentinoids as CaV1.2 channel gating modifiers, and with this uncovered their potential therapeutic application as AADs. However, while efficacious, gabapentinoids also produce undesirable centrally mediated side effects that must be avoided in a well-tolerated chronically dosed AAD. This goal can be achieved through the design of peripherally restricted α2δ-1 ligands, i.e., compounds that are orally bioavailable but not centrally penetrant, which we aim to discover. In preliminary work, Numerate has built predictive computational models for binding to α2δ-1 and for being a substrate for the drug efflux pump P-glycoprotein (P-gp). These models will allow us to efficiently identify compounds that are likely to be peripherally restricted, high-affinity ligands for the gabapentinoid site on α2δ-1. An initial in silico screen of 9 million commercially available compounds identified a series of compounds that are predicted to be ligands for the α2δ channel subunit, and that also have a high likelihood of being peripherally restricted. We will select compounds from this screen for testing. In this SBIR grant proposal Numerate proposes to collaborate with Drs. Hrayr Karagueuzian and Riccardo Olcese at the UCLA Cardiovascular Research Laboratory in order to (1.) discover high-affinity, peripherally restricted α2δ-1 ligands, and (2.) demonstrate their ability to modulate CaV1.2 channel gating and suppress EAD-triggered VT/VF in cell based assays and an isolated intact heart model.

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