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Treatment of Chronic Hypertension; 20-HETE

MCW #1099

 

 Key Inventor

Richard Roman, PhD

 State-of-the-Art

Chronic hypertension is a risk factor for stroke, heart attack, heart failure and arterial aneurysm, and is a leading cause of chronic renal failure. Even moderate increase of arterial blood pressure leads to shortened life expectancy. At severely high blood pressures, defined as mean arterial pressures 50% or more above average, a person can expect to live no more than a few years unless appropriately treated. Studies have indicated that vascular smooth muscle cells in a variety of vascular beds express enzymes of the cytochrome P450 4A and related families (CYP 4A) that catalyze the formation of 20-HETE. In turn 20-HETE is a potent constrictor of renal, cerebral and skeletal muscle arterioles. In the kidney, 20-HETE is also produced by the airways where it serves as a potent endogenously produced bronchodilator.

 Problem

Despite the importance of 20-HETE in the regulation of vascular tone, kidney function, and airway resistance, little is known of its mechanism of action. Understanding the 20-HETE pathway and manipulation of pathway components, especially CYP 4A can lead to inhibitors and antagonists for vasoconstriction control.

 Solution

The current invention is composed of family of analogs that act as 20-HETE antagonists and agonists. An antagonist analog demonstrates the ability to prevent 20-HETE from reducing vascular diameter in a number of different in vivo models. In a reverse manner an agonist analog has shown the ability to reduce vascular diameter or dilate bronchiole smooth muscle. It is suggested that the analog family may be effective in a wide range of 20-HETE regulated diseases.

 Benefit

Diseases thought to be regulated by the 20-HETE pathway are diabetes, end-stage renal disease, toxemia of pregnancy (preeclampsia), polycystic kidney disease, tumor angiogenesis, cerebral vasospasm, stroke, nephrotoxicity, and hypertension.

 Stage of Development

In vivo studies

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MEDICAL COLLEGE OF WISCONSIN
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Summary Information

Patent Status:
6,395,781

Mechanism of Action:
Inhibitor
Antagonist
Agonist

Molecule Type:
Small Molecule

Patent Coverage Type:
Composition of Matter
Method of Use

Geographical Coverage:
Worldwide Patent

Related Areas of Interest:
Cardiovascular

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