The most common form of heart failure is a variant known as heart failure with preserved ejection fraction (HFpEF) and its precursor conditions, diastolic dysfunction, left ventricular hypertrophy with impaired left ventricular relaxation, and infiltrative cardiomyopathy with impaired left ventricular relaxation. HFpEF was previously known as “diastolic heart failure” due to the lack of capacity of the heart to expand adequately and fill during diastole, even though it is capable of contracting appropriately (i.e normal systolic function). HFpEF is almost exclusively a disorder that affects persons over 60 years of age and to this day has no known therapy. Patients suffering from HFpEF and its precursor conditions have a very poor prognosis and there is no redress of this in sight as there have been a series of negative clinical trials and very few large NIH funded studies around the country focused on this disease.
The current management of HFpEF and its precursor conditions is based on therapies known to alleviate symptoms via diuresis and reduce the workload on the heart. These therapies have been mostly tested on the other variant of heart failure (i.e., systolic heart failure, also known as HF with reduced EF) and at best only decrease the symptoms of HFpEF but do not treat the underlying cause as there are no known drug therapies that improve the diastolic function of the heart (though there are many that improve the systolic function). Options for treating patients suffering from HFpEF and its precursor conditions are needed.
The transient receptor potential (TRP) family of ion channels has been studied for many years in the nephrology and neurology literature. Several TRPs have also been found to be important mediators of vascular tone (TRPC1, TRPVc6 and TRPM4), cerebral blood flow (TRPM4), neointimal hyperplasia (TRPC1), and pulmonary hypertension (TRPC6). But until recently, only a few of the channels (such as TRPC3/6/7 in the development of cardiac hypertrophy in response to pressure overload) in this family have been found to have direct cardiac effects. With regards to the transient receptor potential vanilloid (TRPV) family, there are very interesting studies that have found a direct cardiac effect. First, it was observed that cardiac specific overexpression of TRPV2 resulted in chamber dilation of all cavities of the murine heart. Subsequently, it was observed that TRPV1 knockout mice have increased infarct size and decreased survival after ligation of the left anterior descending artery in comparison to their wild type littermates. Interestingly, others have observed that TRPV1 activation with specific agonists results in protection against ischemia/reperfusion (I/R) injury.
Probenecid has recently been identified as being a selective agonist of TRPV2. Probenecid is a highly lipid soluble benzoic acid derivative with an excellent safety profile that was developed in the 1950's to decrease the renal tubular excretion of penicillin; and has been used to increase the serum concentration of several antibiotics and antivirals since. It was also found to be a competitive inhibitor of active transport process in the brain, liver and eye and was studied in these fields but a clinical use was not established outside of its renal effects.
During the initial studies using probenecid (referred to as Benemid), probenecid was observed to have a strong uricosuric effect and quickly became the standard of treatment of gout. It was found to decrease uric acid levels in the serum via inhibition of organic acid reabsorption, such as uric acid, by the renal proximal tube by acting as a competitive inhibitor of the organic anion transporter (OAT) and thus preventing OAT-mediated reuptake of uric acid from the urine to the serum. Even though probenecid has a minimal adverse effect profile, its clinical use has declined significantly as other therapies for gout have shown improved efficacy.
USPTO Backgrounds
USPTO Backgrounds