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In this paper we describe an extensionSAR study of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus as A3AR antagonist.Our initial aim was to replace the phenylcarbamoyl moiety at the 5position of PTP nucleus with a thiourea functionality to evaluatethe contribution of new structural modification against the A3AR. The synthesized 12–25were not characterized by the predicted side chain but by a 1,3-disubstitutedguanidine and are shown to be interesting A3AR antagonists. [ABSTRACT FROM AUTHOR]

Stimulation of A2Aadenosinereceptors (AR) promotesanti-inflammatory responses in animal models of allergic rhinitis,asthma, chronic obstructive pulmonary disease, and rheumatic diseases.Herein we describe the results of a research program aimed at identifyingpotent and selective agonists of the A2AAR as potentialanti-inflammatory agents. The recent crystallographic analysis ofA2AAR agonists and antagonists in complex with the receptorprovided key information on the structural determinants leading toreceptor activation or blocking. In light of this, we designed a newseries of 2-((4-aryl(alkyl)piperazin-1-yl)alkylamino)-5′-N-ethylcarboxamidoadenosines with high A2AAR affinity, activation potency and selectivity obtained by mergingdistinctive structural elements of known agonists and antagonistsof the investigated target. Docking-based SAR optimization allowedus to identify compound 42as one of the most potentand selective A2Aagonist discovered so far (KihA2AAR = 4.8 nM, EC50hA2AAR = 4.9 nM, KihA1AR >10 000nM, KihA3AR = 1487 nM, EC50hA2BAR > 10 000 nM). [ABSTRACT FROM AUTHOR]

A series of 4-allyl/benzyl-7,8-dihydro-8-methyl/ethyl-2-[(substituted)isoxazol/pyrazol-3/5-yl]-1H-imidazo[2,1-i]purin-5(4H)-ones has been synthesized and evaluated in radioligand binding assays to determine their affinities at the human A1, A2A, and A3adenosine receptors. Efficacy at the hA2BAR and antagonism of selected ligands at the hA3AR were also assessed through cAMP experiments. All of the synthesized molecules exhibited high affinity at the hA3AR (Kivalues ranging from 1.46 to 44.8 nM), as well as remarkable selectivity versus A1, A2A, and A2BAR subtypes. Compound (R)-4-allyl-8-ethyl-7,8-dihydro-2-(3-methoxy-1-methyl-1H-pyrazol-5-yl)-1H-imidazo[2,1-i]purin-5(4H)-one (R-33) was found to be the most potent and selective ligand of the series (KihA3= 1.46 nM, KihA2A/KihA3> 3425; IC50hA2B/KihA3> 3425; KihA1/KihA3= 1729). Molecular modeling studies were helpful in rationalizing the available structure–activity relationships along with the selectivity profiles of the new series of ligands. [ABSTRACT FROM AUTHOR]