Purine derivatives as A3 adenosine receptor-selective agonists
Inventors
Jacobson, Kenneth A. • Melman, Artem
Assignees
US Department of Health and Human Services
Publication Number
US-8735407-B2
Publication Date
2014-05-27
Expiration Date
2029-03-24
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Abstract
Disclosed are (N)-methanocarba adenine nucleosides, e.g., of formula (I) as highly potent A3 adenosine receptor agonists, pharmaceutical compositions comprising such nucleosides, and a method of use of these nucleosides, wherein R1-R6 are as defined in the specification. These nucleosides exhibit similar selectivities as agonists of the A3 versus the A1 receptor for both human and mouse adenosine receptors, and are contemplated for use in the treatment a number of diseases, for example, inflammation, cardiac ischemia, stroke, asthma, diabetes, and cardiac arrhythmias.
Core Innovation
The invention provides N-methanocarba adenine nucleosides, exemplified by compounds of formula (I), as highly potent A3 adenosine receptor agonists, pharmaceutical compositions containing such nucleosides, and methods for their use. These nucleosides exhibit selectivity as agonists of the A3 versus A1 adenosine receptors that is consistent for both human and mouse receptors. The compounds include various substituents at defined positions and can be used in pharmaceutical formulations to activate A3 adenosine receptors selectively.
The problem addressed by the invention arises from the limited therapeutic utility of previously known adenosine receptor agonists selective for A1 and A2 receptors due to widespread receptor distribution causing side effects. In contrast, the A3 adenosine receptor has a more limited distribution, primarily in the CNS, brain, testes, and immune system, offering potential for more targeted and effective therapeutic agents. There is therefore an unmet need for A3-selective adenosine receptor agonists with high selectivity over A1 and A2 receptors to alleviate such disadvantages.
The invention solves this problem by providing novel N-methanocarba adenine nucleosides with specific chemical substitutions that impart high potency and selectivity as A3 adenosine receptor agonists. These compounds have demonstrated species-independent selectivity for A3 receptors over A1 receptors in both human and mouse models. The compounds can also be functionalized for drug delivery or linked to various probes or additional pharmacophores, enabling diverse therapeutic and investigative applications.
Claims Coverage
The patent contains two independent claims directed to compounds of Formula I and Formula II with multiple dependent claims covering various substituent variations, compositions, and methods of use. The claims focus on novel chemical structures as selective A3 adenosine receptor agonists, pharmaceutical compositions comprising these compounds, and their use for receptor activation.
A3 adenosine receptor-selective nucleoside compounds of Formula I
The compounds are defined by a purine moiety substituted with specific groups (R1-R5) including various alkyl, aryl, cycloalkyl, and heterocyclic substituents at defined positions, wherein certain provisos restrict combinations of substitutions to achieve selectivity and potency as A3 adenosine receptor agonists. The compounds can exist as pharmaceutically acceptable salts.
A3 adenosine receptor-selective nucleoside compounds of Formula II
A second class of compounds with a purine moiety bearing a benzyl substituent (R6) further substituted with an alkynyl-linked group and other defined groups (R7-R10) at specific positions, selected to optimize receptor affinity and selectivity. These compounds also include pharmaceutically acceptable salts.
Pharmaceutical compositions containing these selective agonists
Compositions comprising an effective amount of the inventive compounds or their salts along with pharmaceutically acceptable carriers, formulated for a variety of administration routes.
Methods for activating A3 adenosine receptors in cells and mammals
Methods involving the administration or contacting of cells or mammals with effective amounts of the inventive compounds to selectively stimulate A3 adenosine receptor-dependent responses, with applicability to therapeutic and research contexts.
The claims collectively cover novel purine derivative compounds selectively agonizing the A3 adenosine receptor through specific structural features, their pharmaceutical compositions, and practical methods of use, emphasizing high potency, species-independent selectivity, and chemical versatility.
Stated Advantages
High selectivity for A3 adenosine receptors over A1 and A2 receptors reduces side effects associated with other receptor subtypes.
Species-independent selectivity makes compounds effective in both human and animal models, aiding translational research and clinical development.
Functionalized derivatives allow covalent attachment of carriers, probes, or other pharmacophores, enabling enhanced drug delivery and multifunctional therapeutic or diagnostic uses.
Pharmaceutical formulations are versatile for various administration routes including oral, parenteral, inhalation, and topical applications.
Documented Applications
Treatment of diseases involving A3 adenosine receptor activation including inflammation, cardiac ischemia, stroke, asthma, diabetes, and cardiac arrhythmias.
Use in treating conditions related to inositol-1,4,5-triphosphate, diacylglycerol release, and arachidonic acid cascade activation such as high blood pressure, locomotor hyperactivity, hypertension, acute hypoxia, depression, and infertility.
Therapeutic and prophylactic treatment of chronic conditions including vascular inflammation, arthritis, allergies, wound healing, acute spinal cord injury, head injury or trauma, seizure, neonatal hypoxia, chronic hypoxia, ischemia and reperfusion injury, severe neurological disorders like Parkinson's and Huntington's diseases, cardiac and kidney diseases, and contraception.
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