426P Granada Congress and Exhibitions Centre
6th European Congress of Pharmacology (EPHAR 2012)



2-Aminopyrimidine derivatives as selective A1 adenosine receptor antagonists

C Val1, J Brea1, E Sotelo2, MI Cadavid1, MI Loza1. 1University of Santiago de Compostela, Department of Pharmacology CP15782, Spain, 2University of Santiago de Compostela, Department of Organic Chemistry CP15782, Spain


The purinic nucleoside adenosine1 modulates a variety of physiological functions within the central nervous system, peripheral nervous system, and tissues through interaction with various receptors located on the cell. Adenosine mediates their effects by activation of a family of four G-protein coupled receptors: A1, A2A, A2B, and A3 2.

Different therapeutic applications have been identified in preclinical and clinical studies for A1 adenosine receptor antagonists, which are effective as potassium-sparing diuretic agents with kidney-protecting properties3. This type of compound is also being tested in the treatment of bradyarrhythmias associated with inferior myocardial infarction, cardiac arrest and cardiac transplant rejection, and could be useful in the treatment of chronic heart diseases4. A1 adenosine receptor antagonists may also offer a therapeutic opportunity for chronic lung diseases such as asthma, chronic obstructive pulmonary disease and pulmonary fibrosis5

Here we describe the identification of 2-Aminopyrimidines as a new family of potent adenosine ligands. Affinities of the new compounds toward human A1, A2A, A2B and A3 adenosine receptors were evaluated by competition experiments assessing their respective abilities to displace [3H]8-cyclopentyl-1,3-dipropylxanthine ([3H]DPCPX) for for A1AR and A2BAR, [3H]4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol ([3H]-ZM241,385) for A2AAR and [3H]adenosine-5’-N-ethylcarboxamide, ([3H]NECA) for A3AR binding. Human adenosine receptors expressed in transfected CHO (A1AR), HeLa (A2AAR and A3AR), and HEK-293 (A2BAR) cells were employed.

From these results we have established a preliminary SAR requirement for activity and selectivity. We obtained some examples of potent ligands (Ki in the low nanomolar range) with variable selectivity profiles in relation to the nature of substituents introduced at C4, C6 and/or amine moiety. We identified compound 2-(ethylamino)-4,6-diphenylpyrimidine-5-carbonitrile as the most active (Ki of 5.82 ± 0.76nM (Ki ± SEM, n=3) in A1 receptor) showing high selectivity over A2A, A2B and A3ARs (21±1, 17±5 and 16±5, %± SEM (percentage displacement of specific binding at 0.1µM (n=2)). It becomes a promising starting point in order to obtain useful hits for the treatment of chronic heart diseases.

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2. Stefano Moro, Zhan-Guo Gao, Kenneth A. Jacobson, Giampiero Spalluto. Medicinal Research Reviews, 2006, Vol. 26, No. 2, 131-159

3. P. S.Modlinger andW. J.Welch, Curr. Opin. Nephrol.Hypertens., 2003, 12, 497–502.

4. R. H. Shah and W. H. Frishman, Cardiol. Rev., 2009, 17, 125–131.

5. C. N. Wilson, A. Nadeem, D. Spina, R. Brown, C. P. Page and S. J. Mustafa, Handb. Exp. Pharmacol., 2009, 193, 329–362.