Adenosine receptor agonists, partial agonists, and antagonists
Inventors
Jacobson, Kenneth A. • Tosh, Dilip K.
Assignees
US Department of Health and Human Services
Publication Number
US-9181253-B2
Publication Date
2015-11-10
Expiration Date
2029-07-31
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Abstract
Disclosed are A3 adenosine receptor antagonists and/or partial agonists and A1 adenosine receptor agonists and/or partial agonists of formula (I): wherein R1 to R5 are as described herein, as well as pharmaceutical compositions thereof and methods of use thereof. The A3 AR antagonists or partial agonists find use in treating a number of diseases such as cancer, glaucoma, and inflammatory diseases, as well as in preventing cardiac ischemia. Also disclosed are radiolabeled compounds of formula (I) and the use thereof in diagnostic imaging of tissues and organs. The A1 AR agonists and partial agonists find use in treating diseases such as seizures, convulsion, stroke, diabetes, pain, arrhythmias, depression, and anxiety and in cardioprotection or neuroprotection.
Core Innovation
The invention relates to compounds that act as A3 adenosine receptor antagonists and/or partial agonists and A1 adenosine receptor agonists and/or partial agonists, described by a specific formula involving substituents R1 to R5 on a purine core. These compounds demonstrate high potency and selectivity toward the A3 adenosine receptor due to a constrained ring or rigid bicyclo[3.1.0]hexane ring at the 9-position of the purine core, with the absence of a substituent at the 4'-position of the bicyclohexane ring leading to a lack of activation of the A3 receptor, often resulting in partial agonism.
The invention addresses the need for new A3 adenosine receptor antagonists and partial agonists, which are desirable as cerebroprotective, antiasthmatic, anti-inflammatory agents, and treatments for diseases such as cancer, glaucoma, and inflammatory diseases, as well as prevention of cardiac ischemia. Similarly, the invention targets full or partial agonists of the A1 adenosine receptor for treating diseases including seizures, stroke, diabetes, pain, arrhythmias, depression, and anxiety, and for cardioprotection or neuroprotection, addressing challenges with existing A1 AR agonists related to peripheral cardiovascular side effects.
Claims Coverage
The patent claims include one independent claim for a compound of formula (I) and cover pharmaceutical compositions and methods of use related to activation of adenosine receptors.
compound of formula (I) with defined substituents
A compound represented by formula (I) with substituents R1 selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, dicycloalkyl C1-C6 alkyl, bicycloalkyl C1-C6 alkyl, tricycloalkyl C1-C6 alkyl, —CH(Ra)(Rb), and C6-C14 aryl C1-C6 alkyl, where Ra and Rb are independently C1-C6 alkyl, C3-C8 cycloalkyl, or C6-C14 aryl. The aryl portion of R1 can be optionally substituted with halo, C1-C6 alkoxy, or halo C1-C6 alkoxy groups.
halo substitution at R2
The substituent R2 of the compound is a halogen, preferably chloro.
hydroxyl substitution at R3 and R4
Substituents R3 and R4 are hydroxyl groups.
hydrogen substitution at R5
Substituent R5 is hydrogen.
pharmaceutical composition containing compound (I)
A pharmaceutical composition comprising the compound or its salt and a pharmaceutically acceptable carrier.
methods for treating diseases by A1 adenosine receptor activation
Methods for treating diseases in a mammal by administering an effective amount of the compound to partially or fully activate an A1 adenosine receptor, providing cardioprotection or neuroprotection specifically in ischemia, seizure, or epilepsy contexts.
The claims collectively cover novel compounds of formula (I) with specific substituents providing activity at A3 and A1 adenosine receptors, pharmaceutical compositions thereof, and therapeutic methods for treating relevant diseases via modulation of these receptors.
Stated Advantages
A3 adenosine receptor partial agonists have less side effects than full agonists and are less likely to cause receptor desensitization, allowing longer duration of action.
The compounds provide high potency and selectivity toward the A3 adenosine receptor.
Certain compounds demonstrate neuroprotection, cardioprotection, and anti-ischemic effects.
The A1 adenosine receptor agonists are highly neuroprotective in ischemic and epileptic models and are being explored for antidepressant, antianxiety, and other neuropsychiatric effects with reduced peripheral cardiovascular side effects.
Compound 121 is more drug-like than prototypical agonist CPA, with better physicochemical properties favoring bioavailability.
Compound 121 shows antiseizure and anticonvulsant properties with lower peripheral toxicity compared to existing compounds.
Documented Applications
Treatment of diseases including cancer, glaucoma, inflammatory diseases, asthma, stroke, myocardial infarction, allergic reactions, rhinitis, poison ivy induced responses, urticaria, scleroderma, arthritis, brain arteriole diameter constriction, bronchoconstriction, and myocardial ischemia by A3 AR antagonists or partial agonists.
Treatment of diseases such as seizures, convulsions, stroke, diabetes, pain, arrhythmias, depression, and anxiety by A1 AR agonists or partial agonists.
Cardioprotection and neuroprotection in ischemia, seizure, or epilepsy via A1 AR activation.
Diagnostic imaging of tissues and organs by administering radiolabeled compounds as probes for the A3 adenosine receptor using techniques such as SPECT, MRS, or PET.
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