Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-11-05
2001-04-03
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06211165
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to therapeutic methods for protecting the heart from ischemic injury. More specifically, the methods of the invention involve administering agonists and antagonists or binary conjugates thereof which selectively activate or inhibit adenosine receptors simultaneously thereby enhancing the protective effects of preconditioning and rendering the myocardium more resistant to ischemia.
BACKGROUND OF THE INVENTION
Several publications are referenced in this application by numerals in parenthesis in order to more fully describe the state of the art to which this invention pertains. Full citations for these references are found at the end of the specification. The disclosure of each of these publications is incorporated by reference herein.
Adenosine is released in large amounts during myocardial ischemia and can mediate potentially A important protective functions in the cardiovascular system (1,4,5,7,9,14, 17,18,19,25). Previous studies have shown that adenosine receptor agonists can precondition the heart when given before the onset of ischemia (4,5,9,14,17,18) and can cause reduction in infarct size or improvement in left ventricular function when given during reperfusion (1,19) or during both low-flow ischemia and reperfusion in isolated perfused heart (6,21,22). While activation of adenosine A1 and A3 receptors has been shown to mimic the cardioprotective effect of preconditioning (3,10,23,24), their roles in mediating the protective effect of adenosine administered during ischemia have not yet been fully elucidated. Further, the cardioprotective effect of exogenous adenosine infused during ischemia in the intact heart may be exerted at the level of coronary vasculature, circulating neutrophils, or cardiac myocytes.
Our previous studies have characterized a cardiac myocyte model of injury, which is induced by exposure of myocytes to prolonged hypoxia in glucose-free media (16,23). Use of this model has facilitated the identification of compounds that enhance the protective effects of preconditioning and also increase myocardial resistance to ischemia.
SUMMARY OF THE INVENTION
The present invention provides methods for preventing or reducing ischemic damage of the heart. In conducting research leading up to this invention, it was discovered that simultaneous activation of A3 and A1 receptors enhances the protective effects of preconditioning and increases myocardial resistance to ischemia. The concept underlying the present invention is the use of specific agonists which simultaneously activate these two adenosine receptors. Concomitant activation of the two receptors is believed to produce a synergistic effect enhancing the cardioprotective effects of preconditioning and increasing myocardial resistance to ischemia.
According to a preferred embodiment, the invention involves administration of specific A1/A3 agonists, such as N
6
-(2-trifluoromethyl)(carbamoyl)adenosine-5′uronamide or N
6
-(3-iodophenyl)(carbamoyl)adenosine-5′uronamide during ischemic attacks, or at risk for ischemic damage. The agonists of the invention may be delivered prior to a surgical procedure. They may also be administered to a patient to prevent or reduce the severity of ischemic damage during surgery. Additionally, the A3/A1 agonists may be administered following surgical procedures to reduce the risk of post-surgical ischemic complications. Finally, the A3/A1 agonists may be administered to patients with angina or to patients during a myocardial infarction. The angina may be chronic and stable, unstable, or post-myocardial infarction angina.
In yet another embodiment of the invention, a series of water-soluble MRS compounds are contemplated to be within the scope of the present invention. These compounds selectively activate the A3 receptor. Because the compounds of the invention do not cross the blood-brain barrier, the deleterious effects associated with A3 receptor activation in the brain are avoided. The MRS compounds will be used in conjunction with the A1 agonists of the invention to prevent or reduce ischemic damage to the heart.
Another preferred embodiment of the invention comprises novel binary conjugates which bind two adenosine receptors simultaneously. Exemplary binary conjugates of the invention contain moieties that act as agonists at both of the A1 and A3 adenosine receptors, such as MRS 1543. A second exemplary conjugate, MRS 1528, acts simultaneously as an agonist at the A3 receptor and as an antagonist at the A2a receptor. Methods are disclosed herein for the administration of these binary conjugates to protect the heart against ischemic damage.
Methods of simultaneous administration of the A3 and A1 agonists or the binary A3 agonist/A2a antagonist or the binary A3 agonist/A1 agonist of the invention include direct perfusion of the organ during surgery and intravenous administration. Additionally, the agonists and antagonists of the invention may be administered to patients in tablet form in an amount effective to prevent or reduce ischemic damage to the heart.
In yet a further aspect of the invention, recombinant myocytes are provided which may be used to advantage in assessing the activity of agents that may possess cardioprotective activity. Cardiac myocytes may be transfected with any of the adenosine receptor encoding cDNAs and used to screen for novel therapeutic agents.
REFERENCES:
patent: 4657897 (1987-04-01), Bristol et al.
patent: 2264949 (1993-09-01), None
Suhaib M. Siddiqi, et al. Search for New Purine-and Ribose-Modified Adenosine Analogues as Selective Agonists and Antagonists at Adenosine Receptors. Journal of Medicinal Chemistry. (Mar. 31, 1995) 1174-1188.
Kenneth A. Jacobson, et al. Structure-Activity Relationships of 9-Alkyladenine and Ribose-Modified Adenosine Derivatives at Rat A3Adenosine Receptors. Journal of Medicinal Chemistry. (May 12, 1995) 1711-1719.
Philip J.M. Van Galen, et al. A Binding Site Model and Structure-Activity Relationships for the Rat A3Adenosine Receptor. Molecular Pharmacology. (1994) 45:1101-1111.
Kenneth A. Jacobson, et al. A Role for Central A3-Adenosine Receptors Mediation of Behavioral Depressant Effects. Federation of European Biochemical Societies. (Dec. 1993) 336,1:57-60.
Qun-Yong Zhou, et al. Molecular Cloning and Characterization of an Adenosine Receptor: The A3Adenosine Receptor. Proc. Natl. Acad. Sci. USA (Aug. 1992) 89:7432-7436.
Vickram Ramkumar, et al. The A3Adenosine Receptor is the Unique Adenosine Receptor Which Facilitates Release of Allergic Mediators in Mast Cells. The Journal of Biological Chemistry. (Aug. 15, 1993) 268,23:16887-16890.
Suhaib M. Siddiqu, et al. Comparative Molecular Field Analysis of Selective A3Adenosine Receptor Agonists. Bioorganic & Medicinal Chemistry. (1995) 3,10: 1331-1343.
Timothy M. Palmer ,et al. Differential Interaction with and Regulation of Multiple G-Proteins by the Rat A3Adenosine Receptor. The Journal of Biological Chemistry. (Jul. 14, 1995) 270,28:1695-16902.
John R. Fozard, et al. The Cardiovascular Effects of Selective Adenosine A1and A2Receptor Agonists in the Pihted Rat: No Role for Glibenclamide-Sensitive Potassium Channels. Nauyn-Schmiedeberg s Archives of Pharmacology. (1993) 347:192-196.
Guang S. Liu, et al. Evidence That the Adenosine A3Receptor May Mediate the Protection Afforded by Preconditioning in the Isolated Rabbit Heart. Cardiovascular Research. (1994) 28:1057-1061.
B.T. Liang. Co-Activation of Adenosine A1and A3Receptors. Acknowledgment 23-24 & 2 sheets of figures. (No date available).
Jennifer Strickler, et al. Direct Preconditioning of Cultured Chick Ventricular Myocytes. J. Clin. Invest. (Oct. 19660 98,8:1773-1779.
Bruce T. Liang. Direct Preconditioning of Cardiac Ventricular Myocytes Via Adenosine A1Receptor and KATPChannel. The American Physiological Society. (1996) 0363-6135, H1769-H1777.
Kenneth A. Jacobson, et al. A3-Adenosine Receptors: Design of Selective Ligands and Therapeutic Prospects. Drugs of the Future. (1995) 20(7): 689-699.
Michel C. Maillard, et al. Adenosine Receptor Prodrugs: Synt
Jacobson Kenneth A.
Liang Bruce T.
Dann, Dorman, Herrell and Skillman
Henley III Raymond
The Trustees of the University of Pennsylvania
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