A3 adenosine receptor agonists
Inventors
Jacobson, Kenneth A. • Tosh, Dilip K. • Salvemini, Daniela
Assignees
St Louis University • US Department of Health and Human Services
Publication Number
US-10577368-B2
Publication Date
2020-03-03
Expiration Date
2034-11-20
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Abstract
Disclosed are compounds of the formula (I) and (II): which are A3 adenosine receptor agonists, pharmaceutical compositions comprising such compounds, and a method of use of these compounds, wherein X, Y, Z, R2-R6, and R103-R106 are as defined in the specification. These compounds are selective to the A3 receptor, and are contemplated for use in the treatment or prevention of a number of diseases or conditions, for example, neuropathic pain.
Core Innovation
The invention provides compounds of formula (I) and (II) that act as A3 adenosine receptor agonists. These compounds are selective to the A3 receptor and are useful in pharmaceutical compositions and methods of use. The compounds have defined chemical structures as set forth in the formulas, including various substitutions for X, Y, Z, R2-R6, and R103-R106 as specified in the description.
The problem being solved addresses the unmet need for effective chronic neuropathic pain treatments. Existing therapies for neuropathic pain are poorly efficacious and have serious side effects, including liver toxicity, addiction, and personality changes. Furthermore, opioids, while effective for acute pain, are not suitable for chronic neuropathic pain due to addiction liability, low efficacy, and the development of tolerance and hypersensitivity. The invention aims at providing compounds with a different mechanism that can be used alone or as adjuncts to opioids to permit effective long-term pain relief without dependence.
The inventive compounds exhibit desirable drug-like properties such as molecular weight less than about 500 Daltons, which supports oral bioavailability. These compounds also possess properties favorable for crossing the blood-brain barrier, thus potentially acting both peripherally and centrally to provide protection against neuropathic pain. The invention also details synthetic pathways for these compounds and compositions comprising such compounds.
Claims Coverage
The patent discloses one independent claim directed to a method for treating pain using compounds of specific defined structures.
Method for treating pain by administering specific A3 adenosine receptor agonist compounds
Administering a therapeutically effective amount of a compound selected from chemically defined A3 adenosine receptor agonists as detailed by the chemical formulas and embodiments of the invention.
Application of specific compounds for treatment of neuropathic pain
Use of selected compounds within the invention specifically to treat neuropathic pain among forms of pain addressed by the method.
The independent claim(s) cover methods of treating pain, particularly neuropathic pain, by administering therapeutically effective amounts of defined selective A3 adenosine receptor agonist compounds according to the detailed chemical formulas disclosed in the invention.
Stated Advantages
The compounds exhibit desirable drug-like physicochemical properties, including molecular weight less than about 500 Daltons, which is expected to confer oral bioavailability.
The compounds possess favorable properties for crossing the blood-brain barrier allowing both peripheral and central action against neuropathic pain.
The compounds provide effective treatment of neuropathic pain with less risk of side effects commonly observed with current therapies such as opioids and other drugs.
The compounds demonstrate synergistic effects in combination with analgesics enhancing potency and potentially reducing required dosages.
Certain compounds show no significant acute liver toxicity and have a high safety margin in animal models.
Documented Applications
Treatment or prevention of neuropathic pain including chronic neuropathic pain associated with various diseases such as diabetes, cancer, injury, AIDS, and Parkinson's disease.
Treatment or prevention of postoperative pain.
Treatment of pain, including neuropathic pain, induced or associated with chemotherapy-induced peripheral neuropathy from various chemotherapeutic regimens.
Use in combination therapy with analgesics such as opioids, antidepressants, antiepileptics, NSAIDs, and calcium channel ligands to provide synergistic pain relief.
Reduction of opioid antinociceptive tolerance and hypersensitivity during opiate therapy for acute or chronic neuropathic pain.
Prevention or treatment of opioid dependence and withdrawal symptoms.
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