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

AuthorsRagusa, Giulio; Gómez-Cañas, María; Morales, Paula ; Rodríguez-Cueto, Carmen; Pazos, M. R.; Asproni, B.; Cichero, E.; Fossa, P.; Pinna, Gerard A.; Jagerovic, Nadine ; Fernández-Ruiz, Javier; Murineddu, Gabriele
Issue Date2017
AbstractIn the last few years, cannabinoid type-2 receptor (CBR) 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 hCBR and hCBR. The 6-(4-chloro-3-methylphenyl)-2-(4-fluorobenzyl)-N-(cis-4-methylcyclohexyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (9) displayed high CB-affinity (KCB = 2.0 ± 0.81 nM) and a notable selectivity (KCB/KCB > 2000). In addition, 9 and other active new synthesized entities have demonstrated to behave as CBR inverse agonists in [S]-GTPγS binding assay. ADME predictions of the newly synthesized CBR 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 CBR ligands.
Identifiersdoi: 10.1016/j.ejmech.2017.01.002
issn: 0223-5234
e-issn: 1768-3254
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