Rational Design of New Drugs to Treat Ventricular Arrhythmias

Information

  • Research Project
  • 8314794
  • ApplicationId
    8314794
  • Core Project Number
    R41HL114206
  • Full Project Number
    1R41HL114206-01
  • Serial Number
    114206
  • FOA Number
    PA-11-097
  • Sub Project Id
  • Project Start Date
    8/21/2012 - 12 years ago
  • Project End Date
    7/31/2014 - 10 years ago
  • Program Officer Name
    BOINEAU, ROBIN
  • Budget Start Date
    8/21/2012 - 12 years ago
  • Budget End Date
    7/31/2014 - 10 years ago
  • Fiscal Year
    2012
  • Support Year
    01
  • Suffix
  • Award Notice Date
    8/20/2012 - 12 years ago
Organizations

Rational Design of New Drugs to Treat Ventricular Arrhythmias

DESCRIPTION (provided by applicant): Sudden cardiac death (SCD) is a major cause of death, responsible for greater than 300,000 adult deaths per year in the United States alone. Cardiac arrest and SCD are caused by ventricular arrhythmias, in particular ventricular fibrillation, which leads to the inability of the heart to circulate blood throughout the body. Approximately 50% of patients suffering from heart failure die as a result of ventricular arrhythmias. Treatment options for the termination or suppression of episodes of ventricular tachycardia include implantable cardioverter-defibrillators (ICD), catheter ablation, and anti-arrhythmic drugs. The efficacy of anti-arrhythmic drugs for the treatment of ventricular tachycardia remains suboptimal, and in some cases their use results in an increased the risk of mortality. There is a clear need for a new innovative approach for developing more effective, specific and safer anti- arrhythmic drugs for the treatment and prevention of ventricular tachycardia. Given the prominent role of RyR2 in the control of Ca2+ homeostasis, pharmacological strategies to modulate RyR2 stability and gating have shown great promise as a therapy for cardiac arrhythmias. Unfortunately, many of the drugs presently used to treat arrhythmias are non-specific in their action. The approach taken in this proposal involves generating a small library of new RyR2 inhibitors with enhanced electron donor properties. This approach is based on our observation that the electron donor properties of drugs targeting RyR2 are prime determinants of the effectiveness of these new molecules. Progress to date demonstrates that new drugs with enhanced electron donor properties act as highly effective inhibitors of RyR2 and as effective inhibitors of arrhythmias in an arrhythmogenic mouse model. The specific aims of this project are as follows: 1) to design and synthesize new RyR2 inhibitors with enhanced electron donor properties. 2) To evaluate the potency of these compounds as electron donors, and as inhibitors of RyR2 at the molecular, cellular and whole animal level. To determine their potency in normalizing Ca2+ homeostasis and decreasing arrhythmias at the cellular, and whole animal level, and to determine the specificity of these new compounds. 3) To evaluate the toxicity of these new drugs in ventricular myocytes. To carry out in vivo and in vitro toxicity studies, and to determine the metabolic stability of these new drugs. Success in phase 1 will be evaluated on the basis of the potency of the new drugs developed in this study. The goal of ELEX Biotech in phase 1 is to develop a group of new drugs which are 100 to 1000 times more effective than our starting compounds in normalizing Ca2+ homeostasis in ventricular myocytes, and decreasing arrhythmias. PUBLIC HEALTH RELEVANCE: Cardiac Arrest and sudden cardiac death caused by arrhythmias is a major cause of death in the United States and in the world. Existing medications tend to be only mildly effective and are relatively non-specific. In order to meet the urgent need for effective therapeutics, ELEX Biotech will create new more potent medications to treat ventricular arrhythmias via a novel approach toward drug design.

IC Name
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
  • Activity
    R41
  • Administering IC
    HL
  • Application Type
    1
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    349774
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    837
  • Ed Inst. Type
  • Funding ICs
    NHLBI:349774\
  • Funding Mechanism
    SBIR-STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    ELEX BIOTECH, LLC
  • Organization Department
  • Organization DUNS
    832476803
  • Organization City
    PORTLAND
  • Organization State
    OR
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    972014830
  • Organization District
    UNITED STATES