Design, Synthesis, and SAR Studies of Heteroarylpyrimidines and Heteroaryltriazines as CB 2 R Ligands

Herein we describe the design and synthesis of a new series of heteroarylpyrimidine/heteroaryltriazine derivatives on the basis of quinazoline‐2,4(1 H ,3 H )‐diones as CB 2 R‐selective ligands using a bioisosterism strategy. An acetamide group was explored to displace the enamine linker of the lead compound for the purpose of stereoisomerism elimination and hydrophilicity increase. As a result, some of the synthesized compounds showed high bioactivity and selectivity for CB 2 R in calcium mobilization assays, and four displayed CB 2 R agonist activity, with EC 50 values below 30 n m . The compound exhibiting the highest agonist activity toward CB 2 R (EC 50 =7.53±3.15 n m ) had a selectivity over CB 1 R of more than 1328‐fold. Moreover, structure–activity relationship (SAR) studies indicated that the substituents on the nucleus play key roles in the functionality of a ligand, with one such example demonstrating CB 2 R antagonist activity. Additionally, molecular docking simulations were conducted with the aim of better understanding of these new derivatives in relation to the structural requirements for agonists/antagonists binding to CB 2 R.