A3 adenosine receptor allosteric modulators
Inventors
Goblyos, Aniko • Brussee, Johannes • Ijzerman, Adriaan P. • Gao, Zhan-Guo • Jacobson, Kenneth
Assignees
Universiteit Leiden • US Department of Health and Human Services
Publication Number
US-8420664-B2
Publication Date
2013-04-16
Expiration Date
2027-01-25
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Abstract
The present invention 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 comprising the same and therapeutic methods comprising administering to a subject an amount of an A3RM, the amount being effective to modulate A3AR activity. The A3RM according to the invention are 1H-Imidazo-[4,5-c]quinolin-4-amine derivatives. The invention also provides some of such novel 1H-Imidazo-[4,5-c]quinolin-4-amine derivatives.
Core Innovation
The invention relates to allosteric modulation of the A3 adenosine receptor (A3AR) and provides the use of A3 adenosine receptor modulators (A3RM), specifically 1H-Imidazo-[4,5-c]quinolin-4-amine derivatives, to prepare pharmaceutical compositions that modulate A3AR activity in a subject. The invention further provides novel derivatives of this chemical class with selective allosteric enhancement properties.
The problem addressed arises from the need for effective therapeutic agents that modulate A3AR, a receptor involved in various physiological processes including tumor growth inhibition and inflammatory diseases. Existing orthosteric agonists have limitations such as side effects and lack of selectivity. The invention offers allosteric modulators that enhance receptor activity, providing potential therapeutic advantages over orthosteric ligands due to greater subtype selectivity and fewer side effects.
Claims Coverage
The patent contains multiple independent claims focusing on methods of treatment using A3AR allosteric enhancers with specific chemical structures and modes of administration. Four main inventive features are identified based on these claims.
Method of treating rheumatoid arthritis by enhancing A3AR activity
A method comprising administering to a subject an effective amount of an A3 adenosine receptor allosteric enhancer that enhances A3AR activity, wherein the enhancer has the specified general formula (I) of 1H-imidazo-[4,5-c]quinolin-4-amine derivatives.
Use of specific imidazoquinoline derivatives as A3AR allosteric enhancers
The allosteric enhancer is selected from a defined list of imidazoquinoline derivatives including N-(4-Methyl-phenyl)-2-cyclopentyl-1H-imidazo[4,5-c]quinolin-4-amine, N-(3,4-Dichloro-phenyl)-2-cyclopentyl-1H-imidazo[4,5-c]quinolin-4-amine, and others, specifying chemical structures enhancing A3AR.
Use of a subgroup of imidazoquinoline derivatives for treatment
A narrower selection of derivatives with superior allosteric modulator activity, including N-(3,4-Dichloro-phenyl)-2-cyclohexyl-1H-imidazo[4,5-c]quinolin-4-amine, is provided as preferred compounds for treatment.
Oral administration for enhancing A3AR activity
The method involves oral administration of the A3AR allosteric enhancers, facilitating practical delivery of the pharmaceutical composition to the subject.
The claims cover methods of treating rheumatoid arthritis by administering effective amounts of novel imidazoquinoline-based allosteric enhancers that modulate A3AR activity, including specific compounds and modes of administration, highlighting selective compounds with potent enhancement effects.
Stated Advantages
A3 adenosine receptor allosteric modulators provide therapeutic advantages over orthosteric agonists, including greater subtype selectivity and fewer side effects.
Allosteric modulators offer a ceiling effect limiting the extent of receptor activation, potentially reducing adverse effects.
Selective affinity for the allosteric site on A3AR minimizes undesired interactions with orthosteric sites of other adenosine receptor subtypes.
The use of microwave irradiation in synthesis reduces reaction time and simplifies purification of imidazoquinoline derivatives.
Modulators enhance efficacy of A3AR activity, leading to modulation of immune functions and reduction in inflammatory disease symptoms such as rheumatoid arthritis.
Documented Applications
Treatment of conditions requiring modulation of A3 adenosine receptor, including hyperproliferative disorders such as solid tumors, skin proliferative diseases, benign hyperplasic disorders, inflammatory diseases like rheumatoid arthritis, Crohn's disease, multiple sclerosis, and ischemic conditions such as myocardial or renal ischemia.
Pharmaceutical compositions for enhancing A3AR activity to treat rheumatoid arthritis.
Modulation of the myeloid system to increase white blood cells and neutrophils, demonstrated in animal models.
Use in treatment of adjuvant induced arthritis (animal model for rheumatoid arthritis) showing reduction in clinical arthritis score.
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