Compositions and methods to treat cardiac diseases
Inventors
Liang, Bruce • Jacobson, Kenneth A. • Joshi, Bhalchandra V. • Kumar, Thatikonda Santhosh
Assignees
University of Connecticut • US Department of Health and Human Services
Publication Number
US-8822434-B2
Publication Date
2014-09-02
Expiration Date
2031-02-22
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Abstract
Phosphonate and phosphinate N-methanocarba derivatives of AMP including their prodrug analogs are described. MRS2339, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) ring system in place of ribose, activates P2X receptors, ligand-gated ion channels. Phosphonate analogs of MRS2339 were synthesized using Michaelis-Arbuzov and Wittig reactions, based on the expectation of increased half-life in vivo due to the stability of the C—P bond. When administered to calsequestrin-overexpressing mice (a genetic model of heart failure) via a mini-osmotic pump (Alzet), some analogs significantly increased intact heart contractile function in vivo, as assessed by echocardiography-derived fractional shortening (FS) as compared to vehicle-infused mice. The range of carbocyclic nucleotide analogs for treatment of heart failure has been expanded.
Core Innovation
The invention relates to phosphonate and phosphinate N-methanocarba derivatives of AMP, including their prodrug analogs, designed to activate P2X receptors, which are ligand-gated ion channels. These derivatives, such as MRS2339, replace ribose with a rigid bicyclo[3.1.0]hexane ring system, increasing stability against enzymatic hydrolysis and improving in vivo half-life due to the stability of the C—P bond. Some analogs, when administered to calsequestrin-overexpressing mice, a genetic model for heart failure, significantly increased intact heart contractile function as measured by echocardiography-derived fractional shortening compared to vehicle-infused mice.
The background describes that extracellular nucleotides mediate cell signaling through purinergic receptors, including P2X receptors that are activated by ATP and have a cardioprotective role. The P2X4 receptor subunit in cardiomyocytes has beneficial effects in models of cardiac hypertrophy and failure, with chronic infusion of nucleotide analogues improving heart function and survival in calsequestrin-overexpressing mice. There is a need for additional myocyte P2X receptor activators with cardioprotective activity.
The summary presents novel phosphonate and phosphinate N-methanocarba derivatives of AMP, with defined structural characteristics, and methods for treating cardiac and vascular diseases responsive to activation of cardiac and/or vascular P2X receptors. These compounds can improve cardiac contractile performance and function, treat cardiac hypertrophy, systolic and diastolic heart failure, ischemic and non-ischemic cardiomyopathy, or adverse remodeling following ischemia/reperfusion injury by administering effective amounts of these derivatives or their prodrug analogs.
Claims Coverage
The patent includes several independent claims focusing on phosphonate or phosphinate N-methanocarba derivatives of AMP and their use in pharmaceutical compositions.
Phosphonate or phosphinate N-methanocarba derivatives of AMP
The invention covers a class of compounds defined by specific chemical formulas (such as Formula I and VII) comprising a bicyclo[3.1.0]hexane ring system replacing ribose, with substituents (Q1, Q2, R1-R5, Y or Y1) as specified, exhibiting stability due to phosphonate or phosphinate groups attached via carbon atoms and optionally having deuterium enrichment or pharmaceutically acceptable salts.
Pharmaceutical compositions containing the phosphonate or phosphinate N-methanocarba derivatives of AMP
The patent claims pharmaceutical compositions comprising the phosphonate or phosphinate N-methanocarba derivatives of AMP along with pharmaceutically acceptable excipients for use in treating cardiac or vascular diseases responsive to activation of cardiac and/or vascular P2X receptors.
The claims broadly cover the novel phosphonate and phosphinate N-methanocarba derivatives of AMP, their various chemical embodiments with defined substituents, and pharmaceutical compositions comprising these derivatives for treating cardiac and vascular conditions.
Stated Advantages
Phosphonate analogs provide increased in vivo half-life due to the stability of the C—P bond.
Compounds show significant improvement in cardiac contractile function and survival in genetic models of heart failure.
The new derivatives eliminate undesired P2Y1 receptor agonist activity, providing more selective activation of cardiac P2X receptors.
Prodrug analogs allow intact passage through the stomach and controlled activation prior to reaching cardiac tissue.
Documented Applications
Treatment of cardiac hypertrophy and cardiac failure resulting from abnormal calcium homeostasis.
Treatment of systolic heart failure, diastolic heart failure, ischemic cardiomyopathy, non-ischemic cardiomyopathy, and adverse remodeling following ischemia/reperfusion injury.
Use as cardioprotective agents to increase survival rates post-myocardial infarction or to prevent cardiac events in high risk patients.
Improvement of cardiac contractile performance and diastolic cardiac muscle relaxation in mammals in need thereof.
Potential treatment of vascular diseases responsive to activation of vascular P2X receptors.
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