Detalle de: Synthesis, Pharmacological Evaluation, and Docking Studies of Novel Pyridazinone‐Based Cannabinoid Receptor Type 2 Ligands

In recent years, cannabinoid type 2 receptors (CB 2 R) have emerged as promising therapeutic targets in a wide variety of diseases. Selective ligands of CB 2 R are devoid of the psychoactive effects typically observed for CB 1 R ligands. Based on our recent studies on a class of pyridazinone 4‐carboxamides, further structural modifications of the pyridazinone core were made to better investigate the structure–activity relationships for this promising scaffold with the aim to develop potent CB 2 R ligands. In binding assays, two of the new synthesized compounds [6‐(3,4‐dichlorophenyl)‐2‐(4‐fluorobenzyl)‐ cis ‐ N ‐(4‐methylcyclohexyl)‐3‐oxo‐2,3‐dihydropyridazine‐4‐carboxamide ( 2 ) and 6‐(4‐chloro‐3‐methylphenyl)‐ cis ‐ N ‐(4‐methylcyclohexyl)‐3‐oxo‐2‐pentyl‐2,3‐dihydropyridazine‐4‐carboxamide ( 22 )] showed high CB 2 R affinity, with K i values of 2.1 and 1.6 n m , respectively. In addition, functional assays of these compounds and other new active related derivatives revealed their pharmacological profiles as CB 2 R inverse agonists. Compound 22 displayed the highest CB 2 R selectivity and potency, presenting a favorable in silico pharmacokinetic profile. Furthermore, a molecular modeling study revealed how 22 produces inverse agonism through blocking the movement of the toggle‐switch residue, W6.48.