- A3 ADENOSINE RECEPTOR ALLOSTERIC MODULATORS
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The present invention provides 2,4-disubstituted quinoline derivatives being an A3 adenosine receptor modulator (A3RM), for use in the treatment of a condition which is treatable by adenosine, an A3 adenosine receptor (A3AR) agonist or an A3 adenosine receptor antagonist. In one embodiment, the 2,4-disubstituted quinoline derivatives are for use in the treatment of a condition treatable by an adenosine or an A3AR agonist, treatment being achieved by enhancing activity of a protein (by binding of said 2,4 disubstituted quinoline derivative to the A3AR). Some conditions treatable by the 2,4 disubstituted quinoline derivative when used for enhancing activity include, malignancy, an immuno-compromised affliction, high intraocular pressure or a condition associated with high intraocular pressure. The invention also provides method for treatment of a subject having a condition treatable by adenosine, an A3AR agonist or an A3AR antagonist making use of the defined 2,4-disubstituted quinoline derivative (s), and pharmaceutical composition and comprising said derivative and a kit comprising the derivative and instructions for use thereof. One specific 2,4-disubstituted quinoline derivative comprises N-{2-[(3,4-dichlorophenyl)amino]quinolin-4-yl}cyclohexanecarboxamide In one embodiment, the 2,4-disubstituted quinoline derivatives in accordance with the invention are formulated in a form suitable for oral administration.
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Page/Page column 30-31
(2010/04/03)
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- A series of 2,4-disubstituted quinolines as a new class of allosteric enhancers of the adenosine A3 receptor
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The adenosine receptor subfamily consists of the adenosine A1, A2A, A2B, and A3 receptors, which are localized in a variety of tissues throughout the human body. It is, therefore, a challenge to develop receptor specific ligands with improved tissue selectivity. Allosteric modulators could have these therapeutic advantages over orthosteric ligands. In the present study, a series of 2,4-disubstituted quinolines were synthesized on the basis of the structure of LUF6000 (34). Compound 27 (LUF6096) was able to allosterically enhance agonist binding to a similar extent as 34. In addition, this new compound showed low, if any, orthosteric affinity for any of the adenosine receptors. In a functional assay, compound 27 showed improved activity in comparison to 34, as it increased both the intrinsic efficacy and the potency of the reference agonist Cl-IB-MECA at the human adenosine A 3 receptor.
- Heitman, Laura H.,G?bly?s, Anikó,Zweemer, Annelien M.,Bakker, Renée,Mulder-Krieger, Thea,Van Veldhoven, Jacobus P. D.,De Vries, Henk,Brussee, Johannes,Ijzerman, Adriaan P.
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supporting information; experimental part
p. 926 - 931
(2010/01/07)
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