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-9963450-B2
Publication Date
2018-05-08
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 the formula (I) and (II) which act as A3 adenosine receptor agonists, pharmaceutical compositions comprising such compounds, and methods for their use. These compounds are selective to the A3 receptor and are contemplated for treating or preventing diseases or conditions exemplified by neuropathic pain. The compounds possess drug-like physicochemical properties that include a molecular weight of less than about 500 Daltons, conferring expected oral bioavailability, and favorable properties for crossing the blood-brain barrier.
The background identifies chronic neuropathic pain (NP) as a widespread condition often associated with diseases such as diabetes, cancer, AIDS, Parkinson's disease, and nerve injury. Existing therapies for NP are poorly efficacious and have serious side effects including liver toxicity, addiction, and personality changes. Treatments commonly involve drugs intended for other conditions, like antidepressants and anticonvulsants, and opioids are not preferred due to addiction liability and low efficacy for chronic pain. Thus, there is an unmet need for novel treatments for chronic neuropathic pain that operate via different mechanisms and can be used alone or with opioids without causing dependence.
Claims Coverage
The patent includes one independent claim defining a compound of formula (I) and one independent claim defining a pharmaceutical composition containing such a compound.
Compound of formula (I)
A compound of formula (I) characterized by various defined substituents including: X selected from NHR1, CH3, and CH═C(Ra)(Rb) where Ra and Rb have specific substituents; R1 selected from a broad range of alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl groups which may be substituted; R2 selected from aryl, cycloalkyl, heteroaryl, and metallocenyl with optional substituents; R3 and R4 independently selected from hydroxyl, amino, mercapto, ureido and others; R5 and R6 with defined substituent options; and pharmaceutically acceptable salts thereof.
Pharmaceutical composition comprising the compound
A pharmaceutical composition comprising a compound or salt of formula (I) and a pharmaceutically acceptable carrier.
The independent claims cover structurally defined A3 adenosine receptor agonist compounds and pharmaceutical compositions containing them, emphasizing specified substituents conferring selectivity and activity, and formulations for therapeutic use.
Stated Advantages
The inventive compounds exhibit desirable drug-like physicochemical properties including molecular weight under about 500 Daltons, expected to confer oral bioavailability.
The compounds possess physicochemical properties favorable for crossing the blood-brain barrier, allowing potential action within the brain.
The compounds show full efficacy in reversing neuropathic pain in vivo with long duration of action for certain analogues.
The compounds demonstrate high specificity for A3 receptor with fewer off-target interactions than prior art compounds.
Certain compounds are highly tolerable and show no significant acute toxicity at high doses in animal models.
Compounds can synergistically enhance analgesic effects of opioids, potentially reinstating opioid efficacy during prolonged use and reducing opioid-related side effects like tolerance and dependence.
Documented Applications
Treatment or prevention of neuropathic pain, including chronic neuropathic pain associated with diabetes, cancer, chemotherapy, and radiation therapy.
Treatment or prevention of postoperative pain.
Treatment or prevention of pain associated with chemotherapy-induced peripheral neuropathy (CIPN) induced by chemotherapeutic drug combinations.
Combination therapy with analgesics, including opioids, antidepressants, antiepileptics, and calcium channel α2δ ligands, for enhanced pain relief and reduction of opioid tolerance and dependence.
Treatment or prevention of opioid dependence and withdrawal symptoms in subjects receiving opiate therapy.
Potential treatment or prevention of various diseases or conditions including vascular inflammation, arthritis, allergies, asthma, wound healing, stroke, cardiac failure, neurological disorders such as Parkinson's disease, Huntington's chorea, diseases of CNS, cardiac and kidney diseases, glaucoma, cancer, dry eye syndrome, inflammatory bowel disease, pulmonary inflammation, uveitis, septic shock, and others as listed.
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