Synthesis and structure activity relationship investigation of triazolo[1,5-a]pyrimidines as CB2 cannabinoid receptor inverse agonists

• Novel triazolo[1,5-a]pyrimidine-6-carboxamide derivatives were synthesized.
• Affinity (Ki, nM) on human CB1 and CB2 receptors of the novel derivatives is reported.
• The most active triazolopyrimidines exhibited greater selectivity than reference compound.
• Introduction of 2-substituents at triazolopyrimidine core changes the functional activity.
• The new ligands were able to significantly increase cAMP production acting as inverse agonists.

CB2 cannabinoid receptor ligands are known to be therapeutically important for the treatment of numerous diseases. Recently, we have identified the heteroaryl-4-oxopyridine/7-oxopyrimidine derivatives as highly potent and selective CB2 receptor ligands, showing that the pharmakodynamics of the new compounds was controlled by the nature of the heterocycle core. In this paper we describe the synthesis and biological evaluation of 7-oxo-4-pentyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide derivatives that led to the identification of novel CB2 receptor inverse agonists. Cyclic AMP experiments on CB2 receptors expressed in CHO cells revealed that introduction of structural modifications at position 2 of triazolopyrimidine template changes the functional activity from partial to inverse agonism. The molecular docking analysis of the novel structures is reported.

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