A3 adenosine receptor agonists and antagonists
Inventors
Jacobson, Kenneth A. • Tosh, Dilip K.
Assignees
US Department of Health and Human Services
Publication Number
US-8916570-B2
Publication Date
2014-12-23
Expiration Date
2029-03-24
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Abstract
Disclosed are (N)-methanocarba adenine nucleosides of formulas (I)-(V), for example, of formula (V): 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 highly potent, selective A3 adenosine receptor agonists, specifically (N)-methanocarba adenine nucleosides of formulas (I)-(V) with various substituents at positions such as 2, N6, 2', 3', 4', and 5'. These nucleosides exhibit similar selectivity as agonists for A3 versus A1 adenosine receptors across human and mouse species. The invention also covers pharmaceutical compositions comprising such nucleosides and methods for selectively activating or inactivating the A3 adenosine receptor in a mammal or cell.
The problem being addressed arises from the limitations of A1 and A2-selective adenosine receptor agents in therapy due to their widespread receptor distribution leading to side effects. The A3 adenosine receptor, with its limited tissue distribution, presents a promising target for therapeutic agents with reduced side effects. There is a need for new selective A3 receptor agonists, including partial agonists that offer cardioprotection with fewer side effects and reduced receptor desensitization, as well as new antagonists useful in cerebroprotection, asthma, inflammation, and glaucoma treatment. Existing literature and patents have not sufficiently addressed this need for novel selective ligands for the A3 receptor.
The invention also describes radiolabeled and isotopically labeled versions of the compounds for diagnostic imaging and receptor distribution studies, taking advantage of the selective binding properties. Methods of synthesis are disclosed, featuring Sonogashira coupling for functionalizing the adenine core, and various substitutions that modulate potency and selectivity. The invention includes compounds acting as full agonists, partial agonists, and antagonists of the A3 adenosine receptor with nanomolar affinity and high selectivity, and methods of treatment covering a broad spectrum of diseases involving the A3 receptor.
Claims Coverage
The patent contains 18 claims including 14 dependent and 4 independent claims providing broad coverage of the compounds of formula (V), their specific substitutions, pharmaceutical compositions, and methods of use.
Compounds of formula (V) with specific substitutions
A compound of formula (V) or pharmaceutically acceptable salts thereof, wherein R301 to R306 and n are selected from defined chemical groups including alkyl, cycloalkyl, aryl, heterocyclyl, with optional substitutions such as halo, amino, hydroxyl, carboxy, aminocarbonyl, and others, and specific preferences for substituents detailed in claims 2 to 11.
Pharmaceutical compositions comprising compounds of formula (V)
Pharmaceutical compositions comprising an effective amount of the compound of formula (V) or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier (claim 14).
Methods of activating A3 adenosine receptor using the compounds
Methods for activating A3 adenosine receptors in mammals or cells by administering or contacting an effective amount of the compounds of formula (V) or salts thereof (claims 15 and 16).
Methods of treating disease states using these compounds
Methods of reducing ischemic damage to the heart and treating diseases, states or conditions such as ischemia and reperfusion injury in skeletal muscle, neuropathic pain, dry eye syndrome, loss of skin pigmentation, pulmonary inflammation, and uveitis by administering effective amounts of compounds of formula (V) or salts thereof (claims 17 and 18).
The claims cover the chemical entities of formula (V) with defined substituents, their pharmaceutical compositions, and methods for receptor activation and therapeutic treatment, focusing on their selective activity at the A3 adenosine receptor and specific medical applications.
Stated Advantages
The compounds exhibit high selectivity as A3 adenosine receptor agonists or antagonists over A1 and A2 receptors.
Partial agonists show cardioprotective, anti-ischemic effects with fewer side effects and reduced receptor desensitization.
Functionalized congeners allow covalent attachment of carriers, probes, or dual pharmacophores, enhancing drug delivery and receptor interaction studies.
Radiolabeled compounds enable diagnostic imaging and determination of drug/tissue distribution.
The limited tissue distribution of the A3 receptor means selective compounds are predicted to have better therapeutic utility with fewer side effects compared to A1 and A2 ligands.
Documented Applications
Treatment of diseases involving inflammation, cardiac ischemia, stroke, asthma, diabetes, cardiac arrhythmias, vascular inflammation, arthritis, allergies, wound healing, acute spinal cord injury, head injury, seizure, cerebral palsy, chronic hypoxia, ischemia and reperfusion injury, neurological disorders including Parkinson's disease and Huntington's chorea, cardiac disease, kidney disease, glaucoma, cancer, neuropathic pain, transient ischemic attacks, myeloprotection, dry eye syndrome, osteoarthritis, rheumatoid arthritis, loss of skin pigmentation, inflammatory bowel disease, pulmonary inflammation, uveitis, and septic shock.
Cardioprotection, specifically preventing or reducing ischemic damage to the heart.
Diagnostic imaging of A3 adenosine receptors in tissues or organs using radiolabeled compounds and imaging techniques such as SPECT, MRS, and PET.
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