Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2001-01-31
2003-03-18
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C514S557000, C514S568000
Reexamination Certificate
active
06534676
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a treatment for patients having congestive heart failure and/or elevated cholesterol blood levels by administering a therapeutically effective amount of 3,5-Diiodothyropropionic acid. The present invention further relates to a synthetic method to prepare 3,5-Diiodothyropropionic acid.
BACKGROUND OF THE INVENTION
Congestive heart failure continues to be a major health problem, affecting about 4.6 million people in the United States, and its prevalence is predicted to increase over the next several decades. The magnitude of heart failure as a clinical problem has placed emphasis on the need to develop new treatment strategies.
One approach that has emerged is the use of thyroid hormone, which has unique physiologic and biochemical actions that make it a novel and potentially useful agent for treatment of heart failure. Thyroid hormone has been shown to act at the transcriptional level on the content of myocardial calcium cycling proteins to stimulate calcium uptake by sarcoplasmic reticulum. In addition, thyroid hormone causes a reciprocal shift in cardiac myosin heavy chain (MHC) isoform expression, increasing the expression of the high activity V
1
isoform and decreasing the low activity V
3
form. These biochemical alterations may underlie the ability of thyroid hormone to increase the rates of ventricular pressure development and relaxation.
Thyroid hormones include the L-forms of thyroxine (3,5,3′5′-L-thyronine; hereinafter thyroxine or T
4
) and triiodothyronine (3′,3,5-L-triiodothyrone; hereinafter triiodothyronine or T
3
). 3′,5′,3-L-Triiodothyronine (hereinafter Reverse T
3
or r T
3
), is a normal metabolite of T
4
. T
4
is synthesized in the thyroid gland and is the circulating form of hormone found in plasma. Although small amounts of T
3
are synthesized by the thyroid gland, the majority is formed from the metabolism of thyroxine in peripheral tissues by the enzyme 5′-monodeiodinase. The molecular basis for the actions of thyroid hormones is though to be mediated through the binding of T
3
to chromatin-bound nuclear receptors. There are two major subtypes of the thyroid hormone receptor, TR&agr; and TR&bgr;, which are the products of two different genes. These genes are members of the c-erbA protooncogene family and are related to a large number of steroid and peptide hormone receptors collectively known as the steroid-thyroid hormone superfamily. The TR &agr; and&bgr; subtypes are differentially expressed in various tissues.
Thyroxine, synthesized by methods such as described in U.S. Pat. No. 2,803,654, is the principle thyroid hormone in current clinical use. This is largely because of its long half-life of 6-7 days. Triiodothyronine, which is less strongly bound to plasma proteins and has a more rapid onset of action, is available for intravenous administration. However, T
3
has a relatively short half-life of two days or less.
Numerous studies have been carried out to synthesize thyroid hormone analogs that mimic the actions of the natural hormones. The objective of most of these efforts has been to develop thyromimetics that lower plasma cholesterol without adverse cardiac effects. A series of thyroxine analogs and methods of synthesis are described in U.S. Pat. No. 3,109,023.
Thyroid hormone agonists that are highly selective for the thyroid hormone receptor &bgr; subtype are described in U.S. Pat. Nos. 5,883,294. 5,284,971 describes a class of thyromimetics, which have the distinguishing characteristic of a sulfonyl bridge in the diphenyl core.
A more recent development has been the use of thyroid hormones for the treatment of cardiovascular compromise. A method for the treatment of patients with sudden (acute) cardiovascular compromise by administration of thyroid hormone is described in U.S. Pat. No. 5,158,978. The method teaches administration of T
4
and T
3
after cardiac arrest by injection into a vein, a central venous catheter, into the pulmonary circulation or directly into the heart.
Short-term intravenous administration of T
3
to patients with advanced congestive failure has been shown to improve cardiac output and decrease arterial vascular resistance. Oral administration of L-thyroxine also has been shown to improve cardiac performance and exercise capacity in patients with idiopathic dilated cardiomyopathy when given for two weeks and 3 months. Although the number of patients in these studies was small, the results were generally favorable and established the basis for further investigation into the safety and potential benefits of treatment of heart failure with thyroid hormone or thyroid hormone analogs.
Because of potential adverse effects of thyroid hormone, such as metabolic stimulation and tachycardia, what is required are thyroid hormone analogs with fewer undesirable side effects. Applicants have found that 3,5-Diiodothyropropionic acid (DITPA) is a thyroid hormone analog that increases cardiac performance with approximately half of the chronotropic effect and less metabolic stimulation than L-thyroxine. Like thyroid hormone, DITPA binds to nuclear T
3
receptors of the c-erbA proto-oncogene family. DITPA has been shown to improve left ventricular (LV) performance in post-infarction experimental models of heart failure when administered alone or in combination with an angiotensin I-converting enzyme inhibitor.
In addition to its well-known chronotropic and inotropic actions on the heart, thyroid hormone decreases arterial resistance, venous resistance and venous compliance. The net effect of these changes is to increase cardiac output more than arterial pressure, resulting in decreased calculated arterial vascular resistance. When used in experimental models of heart failure DITPA acts similarly to thyroid hormone, affecting both the heart and the peripheral circulation. Loss of the normal increase in contractility with heart rate, referred to as the positive force-frequency relationship, has been reported both in failing human myocardium and in animal models of heart failure. DITPA administration prevents the flattened contraction-frequency relationship in single myocytes from infarcted rabbit hearts. DITPA improves myocyte function, enhances calcium transport in the sarcoplasmic reticulum (SR) and prevents the down regulation of SR proteins associated with post-infarction heart failure in rabbits. In normal primates, DITPA enhances the in vivo force-frequency and relaxation-frequency relationships in a manner similar to thyroid hormone. DITPA is able to bring about these hemodynamic changes without increasing cardiac mass appreciably or adversely affecting ventricular dimensions. A morphometric analysis indicates that in post-infarction rats treated with DITPA there is an increase in capillary growth in the border zone around the infarct.
SUMMARY OF THE INVENTION
Applicants have found that 3,5-Diiodothyropropionic acid (DITPA) is a thyroid hormone analog that increases cardiac performance with approximately half of the chronotropic effect and less metabolic stimulation than L-thyroxine. Like thyroid hormone, DITPA binds to nuclear T
3
receptors of the c-erbA proto-oncogene family. DITPA has been shown to improve left ventricular (LV) performance in post-infarction experimental models of heart failure when administered alone or in combination with an angiotensin I-converting enzyme inhibitor.
In addition to its well-known chronotropic and inotropic actions on the heart, thyroid hormone decreases arterial resistance, venous resistance and venous compliance. The net effect of these changes is to increase cardiac output more than arterial pressure, resulting in decreased calculated arterial vascular resistance.
When used in experimental models of heart failure DITPA acts similarly to thyroid hormone, affecting both the heart and the peripheral circulation. Loss of the normal increase in contractility with heart rate, referred to as the positive force-frequency relationship, has been reported both in failing human myocardium and in animal mod
Bahl Joseph J.
Goldman Steven
Morkin Eugene
Pennock Gregory D.
Hayes & Soloway P.C.
Killos Paul J.
The Arizona Board of Regents on Behalf of the University of Ariz
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