Rational Design of New Drugs to Treat Ventricular Arrhythmias

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$349,774.00
Award Year:
2012
Program:
STTR
Phase:
Phase I
Contract:
1R41HL114206-01
Award Id:
n/a
Agency Tracking Number:
R41HL114206
Solicitation Year:
2012
Solicitation Topic Code:
NHLBI
Solicitation Number:
PA11-097
Small Business Information
2828 SW CORBETT AVE, STE 140A, PORTLAND, OR, 97201-4830
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
832476803
Principal Investigator:
JONATHAN ABRAMSON
(503) 725-3014
abramsonj@pdx.edu
Business Contact:
SANDRA SHOTWELL
(503) 771-0173
sandysh@pacifier.com
Research Institute:
PORTLAND STATE UNIVERSITY

PORTLAND STATE UNIVERSITY
BOX 751
PORTLAND, OR, 97207-
() -
Nonprofit college or university
Abstract
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 insome 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 thenew 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. Inorder 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.

* information listed above is at the time of submission.

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