A novel class of 2-acylamino-cycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as potent TMEM16A inhibitors

UCSF researchers have invented a novel method to generate covalent macromolecular inhibitors. This strategy allows a peptide inhibitor to bind to its target protein specifically and irreversibly through proximity-enabled bioreactivity.

This invention describes an orientation-independent device that can create bright and highly localized signal enhancement during magnetic resonance imaging.

Using an alpha-1A-adrengic receptor agonist, dabuzalgron, as a therapeutic treatment for cardiomyopathy and heart failure.

This invention identifies a method to accurately measure flow dynamics, such as velocity and volume, from Computed Tomography scans of blood vessels in a patient.

Therapeutic inhibitors of Urea Transporter A (UT-A) as highly effective diuretics with reduced risk of cardiac and neurological side effects for treatment of cardiovascular and renal disorders

This invention consists of the use of a novel class(es) of anti-inflammatory and pro-resolving mediators derived from ω-3 polyunsaturated fatty acids, as well as devices designed to deliver these mediators directly to blood vessel for therapeutic modulation of blood vessel healing.

This invention consists of a novel peptide-modified thermo-reversible methylcellulose (MC) that has the therapeutic potential to repair chronic ischemic cardiomyopathy.

Over 5 million Americans currently suffer with congestive heart failure and despite aggressive medical therapies targeted to treat this disease; the outlook for these patients remains grim, with estimated mortalities of 33% and 50% at 1 and 5 years, respectively. Congestive heart failure (CHF) remains a significant unmet need in the global medical community. A treatment option for CHF by cellular transplantation of stem cells is a developing research area. This approach has been studied using fetal cardiomyocytes, adult skeletal muscle cells, autologous bone marrow-derived mesenchymal stem cells, cardiac progenitor (CP) cells, and cardiomyocytes derived from embryonic stem cells. However, current studies have yielded modest results in reducing infarct size and scar tissue. Furthermore, the necrotic/apoptotic loss of the vast majority of donor cells within days after transplantation is a major drawback. 

Anthracyclines are the most commonly prescribed chemotherapeutic agent for their effectiveness in treating cancer.  However use of anthracyclines can have the severe, adverse effect of cardiac toxicity leading to cardiomyopathy and clinical heart failure.  Currently available medications to counteract anthracycline-induced cardiotoxicity either do so at the cost of anti-tumor activity, or there is insufficient clinical trial data to support their efficacy in preventing cardiotoxicity.  Thus widespread use of these compounds is limited.    There is a clinical need for a pharmaceutical compound that can prevent and/or treat the cardiac side effects of anthracyclines while maintaining their anti-tumor activity.

Myocardial infarction (MI) is a leading cause of cardiovascular diseases worldwide.  There are five million people that suffer from heart failure in the United States alone at a cost of $30 billion per year.  MI often results in scar formation and death of contracting heart muscle cells (cardiomyocytes).  The subsequent scarring of cardiomyocytes will permanently damage a patient's heart, leading to a life threatening heart rate disorder (arrhythmia).  Despite therapeutic advances in heart disease, there are currently no treatments that can replace scarred cardiomyocytes with functional ones.

Brief description not available

Patients suffering from moderate to severe cardiac failure can enjoy substantial improvements in quality of life and survival, when provided with cardiac resynchronization therapy (CRT). However, this treatment has a 30% failure rate due in part to difficulties in characterizing intraventricular synchrony. Improvements in methodology could lead to appropriate patient selection and improved pacemaker positioning, resulting in enhanced therapeutic effectiveness. To redress these problems, UCSF researchers have developed software that permits the visualization and quantification of relevant parameters using a number of different imaging tools. Their novel method employs first harmonic imaging to the blood pool study, yielding a quantitative basis for treatment and evaluation.

Obesity, an epidemic problem in the US population, has been linked to several major medical problems, including diabetes, stroke, heart disease, high blood pressure and even cancer. Determinants of obesity are complex and genetics account for approximately 25-40% of cases. Although there is great emphasis on discovering the underlying genetic basis for predisposition to obesity, much remains unknown. As a result, there does not yet exist a safe, effective and proven therapy for treatment of obesity.UCSF investigators have developed a new mouse model of obesity. They have generated a transgenic mouse with a hypomorphic allele of the receptor tyrosine kinase TrkB. TrkB is expressed throughout the brain, including the hypothalamus, the center known to control eating behavior. These transgenic mice express TrkB protein at 24% of normal levels in the hypothalamus, and display a maturity onset obesity syndrome. By 12 weeks of age the mutant mice exhibit significant weight gain compared to their wildtype littermates and display hyperphagia as well as significantly increased levels of insulin and leptin in the bloodstream. A similar phenotype has been observed in mice with only one functional allele of BDNF, a ligand of the TrkB receptor (Kernie et al., EMBO J., 2000, 19:1290-1300). These phenotypes parallel those observed in human obesity, indicating that the BDNF/TrkB interaction is a potential target for the development of treatments for obesity and that the TrkB transgenic mice represent a valuable model for studying the development of obesity.

Volume over-load conditions, such as congestive heart failure, cirrhosis, nephrotic syndrome, and volume-sensitive hypertension are often treated with a battery of different types of diuretics, such as loop diuretics, thiazides, and K-sparing diuretics that affect different functions of the kidney.  However, some of these diuretics, particularly thiazides, cause unwanted side-effects, such as potassium imbalance or acid-base disorders.  Diuretics also have limited efficacy in some conditions (e.g., diuretic-refractory edema in congestive heart failure). Recent studies suggest that drugs designed to inhibit urea transporters (a.k.a. "urearetics") in the kidney could be used to treat water and salt imbalance disorders.  Urea transporters play a role in concentrating urea in the urine and thus affect water and salt concentrations.  One potential advantage of urearetics is that they are unlikely to cause secondary potassium imbalance or acid-base disorders.  Unfortunately, potent and specific urea transporter inhibitors have not been available.