A3 adenosine receptor allosteric modulators
Inventors
GÖBLYÖS, Anikó • Brussee, Johannes • Ijzerman, Adriaan P. • Gao, Zhan-Guo • Jacobson, Kenneth
Assignees
Universiteit Leiden • US Department of Health and Human Services
Publication Number
US-9326978-B2
Publication Date
2016-05-03
Expiration Date
2027-01-25
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Abstract
The claimed subject matter relates to allosteric modulation of A3 adenosine receptor (A3AR) and provides for the use of an A3 adenosine receptor modulator (A3RM), for the preparation of pharmaceutical compositions for modulating the A3AR in a subject, as well as pharmaceutical compositions including the same and therapeutic methods including administering to a subject an amount of an A3RM, the amount being effective to modulate A3AR activity. The A3RM according to claimed subject matter are 1H-Imidazo-[4,5-c]quinolin-4-amine derivatives. Also provided are 1H-Imidazo-[4,5-c]quinolin-4-amine derivatives.
Core Innovation
The invention relates to allosteric modulation of the A3 adenosine receptor (A3AR) using specific imidazoquinoline derivatives. These compounds are described as A3 adenosine receptor modulators (A3RM) with a general chemical formula and specific substituents. The invention provides pharmaceutical compositions containing these modulators and methods of modulating A3AR activity in subjects by administering effective amounts of these compounds.
The problem addressed is the need for selective modulation of A3AR to treat various conditions while avoiding the limitations of orthosteric agonists or antagonists. A3AR is highly expressed in tumor cells compared to normal cells and is involved in physiological processes including tumor growth inhibition and inflammation modulation. Allosteric modulators offer potential therapeutic advantages such as greater subtype selectivity, fewer side effects, and a ceiling effect on receptor activity.
The invention discloses novel 1H-Imidazo-[4,5-c]quinolin-4-amine derivatives that selectively bind to the allosteric site of human A3AR, enhancing receptor activity by increasing efficacy and decreasing dissociation of orthosteric agonists. The compounds exhibit low affinity to orthosteric binding sites of A1, A2A, and A2B adenosine receptors, providing specificity. The invention also demonstrates pharmaceutical uses of these modulators in treating conditions requiring A3AR modulation, with preferred oral administration and possible combination with orthosteric ligands.
Claims Coverage
The patent includes two independent claims covering specific imidazoquinoline derivatives and their pharmaceutical compositions. These claims focus on compounds of defined chemical structures as A3AR allosteric modulators and their use in pharmaceutical formulations.
Imidazoquinoline derivatives as selective A3AR allosteric modulators
The compounds defined have specific chemical structures of N-substituted 1H-imidazo[4,5-c]quinolin-4-amines with various substituents, particularly containing 3,4-dichlorophenyl or related groups. These derivatives exhibit selective affinity for the allosteric site of human A3AR, with low or no affinity for orthosteric sites of other adenosine receptor subtypes.
Pharmaceutical compositions containing the defined imidazoquinoline derivatives
Pharmaceutical compositions comprising as active ingredients the claimed imidazoquinoline derivatives along with pharmaceutically acceptable excipients are covered. Preferred compositions are suitable for oral administration and contain selected compounds with demonstrated allosteric enhancement properties.
The claims define novel imidazoquinoline derivatives that selectively modulate A3AR allosterically and pharmaceutical compositions including these compounds. The scope covers specific chemical entities and compositions for therapeutic modulation of A3AR activity.
Stated Advantages
Allosteric modulators provide greater subtype selectivity and fewer side effects compared to orthosteric agonists.
The selective affinity for the allosteric site of A3AR avoids interaction with orthosteric sites on other adenosine receptor subtypes, enhancing specificity.
A ceiling level to the allosteric effect reduces the risk of overstimulation or desensitization of the receptor.
Modulators can increase the efficacy of A3AR and decrease agonist dissociation rate, enhancing therapeutic benefits.
Microwave-assisted synthesis reduces reaction time and simplifies purification of the compounds.
Documented Applications
Treatment of various cancers including colon, prostate, pancreatic carcinomas, melanoma, hepatoma, and metastatic tumors by modulation of A3AR.
Treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and multiple sclerosis through anti-inflammatory effects via A3AR modulation.
Possible treatment of benign hyperplasic disorders like benign prostate hyperplasia and non-tumorigenic polyps.
Therapy of ischemic conditions such as myocardial and renal ischemia by enhancing A3AR activity.
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