Composition and methods to treat cardiac diseases
AssigneeUniversity of Connecticut
InventorsBruce Tsan Liang, Achilles Pappano, Jian-Bing Shen
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Abstract
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 Ca2+ 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.
Claims14
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:
- R1 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
- R2 is hydrogen, halogen, thiol, cyano, alkyl, alkenyl, alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, arylamino, or aryloxy;
- R3 is hydrogen, halogen, methyl, or ethyl;
- and
- R4 and R5 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.
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:
- R1 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
- R2 is hydrogen, halogen, thiol, cyano, alkyl, alkenyl, alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, arylamino, or aryloxy;
- R3 is hydrogen, halogen, methyl, or ethyl;
- and
- R4 and R5 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.
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:
- R1 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
- R2 is hydrogen, halogen, thiol, cyano, alkyl, alkenyl, alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, arylamino, or aryloxy;
- R3 is hydrogen, halogen, methyl, or ethyl;
- and
- R4 and R5 are independently hydrogen, methyl, or methoxy.
Dependencies are inferred from the claim text.