Composition and methods to treat cardiac diseases
Disclosed herein are N-methanocarba derivatives of AMP and their use in the treatment of cardiac and vascular diseases and conditions responsive to activation of the cardiac P2X receptor. In one embodiment, the N-methanocarba derivative of AMP is the N-methanocarba derivative of 2-chloro-AMP. Diseases and conditions responsive to activation of the cardiac P2X receptor include, for example, cardiac hypertrophy, cardiac failure resulting from any cause of abnormal Ca 2+ homeostasis or from myocardial injuries, vascular insufficiency leading to myocardial infarction, post-myocardial infarction conditions, post-myocardial infarction conditions within the short-term post-infarction period, and diastolic heart failure.
1. A method of treating a mammalian subject in need of treatment for a cardiac or vascular disease or condition responsive to activation of the cardiac P2X receptor, comprising
administering an effective amount of an N-methanocarba derivative of AMP that activates a cardiac P2X receptor for the treatment of the cardiac or vascular disease or condition responsive to activation of the cardiac P2X receptor,
wherein the N-methanocarba derivative of AMP that activates the cardiac P2X receptor is of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, alkyl, alkoxy, amino, mono- or di-alkylamino, mono or bicyclic cycloalkyl, cycloalkyloxy, aryl, arylalkyl, acyl, sulfonyl, arylsulfonyl, or a mono- or bicyclic thiazolyl group; and
R 2 is hydrogen, halogen, thiol, cyano, alkyl, alkenyl, alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, arylamino, or aryloxy;
R 3 is hydrogen, halogen, methyl, or ethyl; and
R 4 and R 5 are independently hydrogen, methyl, or methoxy,
wherein the cardiac or vascular disease or condition responsive to activation of the cardiac P2X receptor is a post-myocardial infarction condition, or diastolic heart failure.
2. The method of claim 1 , wherein
R 1 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, mono- or di-C 1 -C 4 alkylamino, C 3 -C 7 cycloalkyl, or C 3 -C 7 cycloalkyloxy;
R 2 is hydrogen, halogen, thiol, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, or C 1 -C 4 alkylsulfonyl; and
R 3 , R 4 , and R 5 are all hydrogen.
3. The method of claim 1 , wherein
R 1 is NH 2 or CH 3 NH;
R 2 is H, Cl, SCH 3 or SOCH 3 ; and
R 3 , R 4 , and R 5 are all hydrogen.
4. The method of claim 1 , wherein the N-methanocarba derivative of AMP is
5. The method of claim 1 , wherein the post-myocardial infarction condition is post-myocardial infarction conditions within the short-term post-infarction period.
6. The method of claim 1 , further comprising administering a beta-adrenergic blocker, an angiotension receptor blocker, or an angiotensin converting enzyme blocker.
7. The method of claim 1 , wherein the post-myocardial infarction condition is ischemic cardiomyopathy.
8. A method of improving cardiac contractile performance in a mammal in need thereof, comprising
administering an effective amount of an N-methanocarba derivative of AMP that activates a cardiac P2X receptor for improving cardiac contractile performance, wherein the N-methanocarba derivative of AMP that activates a cardiac P2X receptor is of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, alkyl, alkoxy, amino, mono- or di-alkylamino, mono or bicyclic cycloalkyl, cycloalkyloxy, aryl, arylalkyl, acyl, sulfonyl, arylsulfonyl, or a mono- or bicyclic thiazolyl group; and
R 2 is hydrogen, halogen, thiol, cyano, alkyl, alkenyl, alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, arylamino, or aryloxy;
R 3 is hydrogen, halogen, methyl, or ethyl; and
R 4 and R 5 are independently hydrogen, methyl, or methoxy,
wherein the mammal has had a myocardial infarction, or wherein the mammal is in need of treatment for diastolic heart failure.
9. The method of claim 8 , wherein
R 1 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, mono- or di-C 1 -C 4 alkylamino, C 3 -C 7 cycloalkyl, or C 3 -C 7 cycloalkyloxy;
R 2 is hydrogen, halogen, thiol, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, or C 1 -C 4 alkylsulfonyl; and
R 3 , R 4 , and R 5 are all hydrogen.
10. The method of claim 8 , wherein administering is performed within the short-term post-infarction period.
11. The method of claim 8 , wherein the N-methanocarba derivative of AMP is a compound of the formula:
12. The method of claim 8 , wherein the post-myocardial infarction condition is ischemic cardiomyopathy.
13. A method of treating a mammalian subject in need of treatment for a cardiac hypertrophy, comprising
administering an effective amount of a cardiac P2X receptor agonist,
wherein the N-methanocarba derivative of AMP is a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, alkyl, alkoxy, amino, mono- or di-alkylamino, mono or bicyclic cycloalkyl, cycloalkyloxy, aryl, arylalkyl, acyl, sulfonyl, arylsulfonyl, or a mono- or bicyclic thiazolyl group; and
R 2 is hydrogen, halogen, thiol, cyano, alkyl, alkenyl, alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, arylamino, or aryloxy;
R 3 is hydrogen, halogen, methyl, or ethyl; and
R 4 and R 5 are independently hydrogen, methyl, or methoxy.
14. The method of claim 13 , wherein the N-methanocarba derivative of AMP is a compound of the formula: