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

Giulio Ragusa; Serena Bencivenni; Paula Morales; Tyra Callaway; Dow P. Hurst; Battistina Asproni; Stefania Merighi; Giovanni Loriga; Gerard A. Pinna; Patricia H. Reggio; Stefania Gessi; Gabriele Murineddu

Index: 10.1002/cmdc.201800152

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Abstract

In recent years, cannabinoid type 2 receptors (CB2R) have emerged as promising therapeutic targets in a wide variety of diseases. Selective ligands of CB2R are devoid of the psychoactive effects typically observed for CB1R 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 CB2R 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 CB2R affinity, with Ki values of 2.1 and 1.6 nm, respectively. In addition, functional assays of these compounds and other new active related derivatives revealed their pharmacological profiles as CB2R inverse agonists. Compound 22 displayed the highest CB2R 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.