Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-15
2002-01-29
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S307000
Reexamination Certificate
active
06342495
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns the use of agonists and antagonists of the peripheral-type benzodiazepine receptors (PTBRs). More particularly, the invention concerns the use of PTBR agonists and antagonists (including PTBR ligands) in the diagnosis and treatment of cardiac hypertrophy and other circulatory conditions.
BACKGROUND OF THE INVENTION
In response to hormonal, physiological, hemodynamic and pathological stimuli, adult ventricular muscle cells can adapt to increased workloads through the activation of a hypertrophic process. This process is characterized by an increase in the contractile protein content of cardiac muscle cells without a proliferative response because the adult cardiomyocyte is terminally differentiated and has lost its ability to divide. Cardiac growth during the hypertrophic process therefore results primarily from an increase in protein content per individual cardiomyocyte, with little or no change in cell number. The acquisition of the cardiac hypertrophic phenotype is in part dependent upon the activation of cardiac muscle gene program.
In addition to the induction of specific contractile protein components, ventricular hypertrophy is also characterized by alterations in the expression of certain non-contractile proteins, such as atrial natriuretic peptide (ANP, also known as ANF). During embryonic development, the ANP gene is expressed in both the atrium and the ventricle. However, shortly after birth ANP expression is down regulated in the ventricle and expression is mainly confined to the atrium. Following induction of hypertrophy, ANP is reexpressed in the ventriculum. Thus, ANP expression can be considered to be a non-contractile protein marker of cardiac ventricular hypertrophy.
Ventricular hypertrophy is initially a compensatory mechanism by which the heart is attempting to counteract the effects of conditions like pressure overload, loss of contractile tissue, obstruction of blood flow, or increased peripheral demand for blood flow, all of which can be generated by a variety of physiological or pathological stimuli. In some circumstances, such as, injury or functional compromise of the heart, a typically short term, compensated hypertrophic response is desirable. Similarly, cardiac, e.g. left ventricular, hypertrophy (physiological hypertrophy) is often observed in some highly trained athletes, without any apparent cardiovascular complications. However, under some circumstances the hypertrophic response may eventually contribute to cardiac dysfunction. These circumstances include, but are not limited to, excessive hypertrophy, prolonged hypertrophy, or hypertrophy occurring in the context of toxic factors or toxic concentrations of factors that, when combined with the hypertrophic response of cardiac myocytes, result in mechanical dysfunction, electrical conduction dysfunction, loss of cardiac wall elasticity, or stimulation of fibrosis. In these cases hypertrophy is termed decompensated hypertrophy, and antagonism of cardiac hypertrophy is considered desirable. Once the transition from compensated to decompensated hypertrophy is achieved, the progression to a terminal heart failure phenotype often rapidly follows.
Heart failure affects approximately five million Americans. New cases of heart failure number about 400,000 each year. The pathophysiology of congestive heart failure is rather complex. In general, congestive heart failure is a syndrome characterized by left ventricular dysfunction, reduced exercise tolerance, impaired quality of life, and markedly shortened life expectancy. Decreased contractility of the left ventricle leads to reduced cardiac output with consequent systemic arterial and venous vasoconstriction. This vasoconstriction, which promotes the vicious cycle of further reductions of stroke volume followed by an increased elevation of vascular resistance, appears to be mediated, in part, by the renin-angiotensin system. Numerous etiologies contribute to the development of CHF, including primary diseases of, or insults to, the myocardium itself, cardiac defects, hypertension, inflammation, kidney disease and vascular disease. These conditions lead to the hypertrophy and remodeling of the cardiac ventricles which, if unchecked, ultimately reduce the mechanical performance of the heart. Forces associated with the inability of the heart to pump blood ultimately lead to the release of neurohormones like catecholamines, renin-angiotensin, aldosterone, endothelin and related factors into the circulation. It has been demonstrated that elevations in plasma levels of many of these circulating neurohoiiones may have a deleterious impact on the outcome of patients with CHF. Local production of these neurohormonal factors in the heart is believed to contribute centrally to the disease. Thus, an important therapeutic strategy has been to block this neurohormonal axis contributing to the pathogenesis of this disease.
Factors known to contribute centrally to the pathophysiology of heart disease are biosynthesized in the heart itself. These factors are produced in cardiac myocytes, fibroblasts, smooth muscle and endothelial cells, and inflammatory cells associated with the myocardium. For example, the heart has been shown to contain its own renin-angiotensin system. Blockade of the cardiac renin-angiotensin system is believed to contribute significantly to the therapeutic efficacy of the therapeutic class of agents known as angiotensin converting enzyme (ACE) inhibitors.
The heart also produces other factors including, but not limited to, endothelins, bradykinin, adrenomedullin, tumor necrosis factor, transforming growth factors, and natriuretic peptides. While there are successful therapeutic approaches based on the modulation of these secondary factors, there is a need for devising different strategies that directly modulate the cardiac hypertrophic response.
Thus, there is a great interest in trying to understand the mechanisms that induce and control ventricular hypertrophy and indeed to dissect the transition from compensated to decompensated hypertrophy. There are several physiological stimuli that will induce a hypertrophic response in isolated cardiomyocytes such as endothelin-1, TGF-&bgr; and angiotensin II. Additionally, the &agr; adrenergic agonist phenylephrine is a well-characterized and potent inducer of hypertrophy in isolated cardiomyocytes.
In the course of our functional genomic studies, the gene of a peripheral-type benzodiazepine receptor (PTBR) was found to be differentially expressed in the hearts of several rat models of heart failure. Peripheral-type benzodiazepine receptors represent a subset of the benzodiazcpine receptor family distinguished by their location outside the central nervous system (CNS). A review of PTBR's, including the molecular structure, biological properties and possible physiological roles has been published by Zisterer and Williams,
Gen. Pharmac.
29:305-314 (1997), the entire disclosure of which is hereby expressly incorporated by reference.
Ligands of PTBR's have been known for many years and anti-depressant CNS effects of PTBR agonists (e.g. Valium) are widely known. Vagal tone has been found to decrease following intravenous administration of diazepam (Adinoff et al.,
Psychiatry Research
41:89-97 [1992]). There is evidence for control of cardiac vagal tone by benzodiazcpine receptors (DiMicco,
Neurophaimacology
26:553-559 [1987]). PTBR ligands Ro5-4864 and PK11195, but not diazepam, have been described to depress cardiac function in an isolated working rat heart model (Edoute et al.,
Pharmacology
46:224-230 [1993]). Ro5-4864 has also been reported to increase coronary flow in an isolated perfused Langendorf rat heart without affecting heart rate and left ventricular contractility. PK11195 did not antagonize this vasodilatory effect (Grupp et al.,
Eur. J. Pharm.
143:143-147 [1987]). In an isolated rat heart preparation, diazepam induced a transient negative inotropic effect followed by a positive inotropic
Joly Alison
Schreiner George F.
Stanton Lawrence W.
White R. Tyler
Henley III Raymond
Knobbe Martens Olson & Bear LLP
Scios Inc.
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