Development of novel compounds for the treatment of atrial fibrillation

DESCRIPTION provided by applicant Atrial fibrillation AF is the most prevalent type of cardiac arrhythmia in the developed world affecting million people in the United States alone a number that is expected to double by because of population aging Current pharmacological options are ineffective which may be in part because these drugs fail to target key pathogenic mechanisms Recent work has shown that dysfunction of the cardiac ryanodine receptor RyR plays a central role in AF pathogenesis Diastolic leak of calcium Ca via RyR can initiate triggered activity which can initiate new AF episodes and can also promote atrial remodeling underlying the perpetuation of AF Our long term goal is to develop potent anti arrhythmic drugs to treat AF and other arrhythmias The objective is to obtain pre clinical data showing that Elex Biotechandapos s promising new lead compounds embody effective pharmaceuticals for the treatment of AF Our central hypothesis is that drugs with enhanced electron donor properties that target RyR will be highly effective in decreasing the SR Ca leak associated with atrial arrhythmias Building on our recent work demonstrating anti arrhythmic properties in animal models of ventricular tachycardia we will test our compounds in clinically relevant animal models of AF In Specific Aim we will optimize lead compounds using an SAR evaluation based on in vitro assays In Specific Aim we will perform a preclinical evaluation of lead drug candidates in a mouse model of progressive AF In Specific Aim we will characterize the effects of novel RyR inhibitors on AF in tachypaced rabbits Significance These studies are expected to identify outstanding leads for further pre clinical studies e g large animal models of AF and eventual clinical development Compound selection will be based on potency defined as equal or better than and IC andlt nM for inhibition of Ca spark frequency in atrial myocytes and in vivo efficacy at andlt g kg or less in a mouse model of AF PUBLIC HEALTH RELEVANCE The proposed work will study how the novel compounds that inhibit the calcium release channel ryanodine receptor suppress abnormal intracellular calcium release in animal models of atrial fibrillation the most common sustained cardiac arrhythmia in the US