New pyridazinone-4-carboxamides as new cannabinoid receptor type-2 inverse agonists: Synthesis, pharmacological data and molecular docking

Abstract In the last few years, cannabinoid type-2 receptor (CB 2 R) selective ligands have shown a great potential as novel therapeutic drugs in several diseases. With the aim of discovering new selective cannabinoid ligands, a series of pyridazinone-4-carboxamides was designed and synthesized, and the new derivatives tested for their affinity toward the h CB 1 R and h CB 2 R. The 6-(4-chloro-3-methylphenyl)-2-(4-fluorobenzyl)- N -( cis- 4-methylcyclohexyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide ( 9 ) displayed high CB 2 -affinity ( K i CB 2  = 2.0 ± 0.81 nM) and a notable selectivity ( K i CB 1 / K i CB 2  > 2000). In addition, 9 and other active new synthesized entities have demonstrated to behave as CB 2 R inverse agonists in [ 35 S]-GTPγS binding assay. ADME predictions of the newly synthesized CB 2 R ligands suggest a favourable pharmacokinetic profile. Docking studies disclosed the specific pattern of interactions of these derivatives. Our results support that pyridazinone-4-carboxamides represent a new promising scaffold for the development of potent and selective CB 2 R ligands.