title: 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 (CB2R) 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 hCB1R and hCB2R. The 6-(4-chloro-3-methylphenyl)-2-(4-fluorobenzyl)-N-(cis-4-methylcyclohexyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (9) displayed high CB2-affinity (KiCB2= 2.0 ± 0.81 nM) and a notable selectivity (KiCB1/KiCB2> 2000). In addition, 9 and other active new synthesized entities have demonstrated to behave as CB2R inverse agonists in [35S]-GTPγS binding assay. ADME predictions of the newly synthesized CB2R 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 CB2R ligands.
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, via F. Muroni 23/A, 07100, Sassari, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Ragusa
authors.affiliation: Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040, Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Gómez-Cañas
authors.affiliation: Instituto de Química Médica, CSIC, Calle Juan de la Cierva, 3, 28006, Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Morales
authors.affiliation: Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040, Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Rodríguez-Cueto
authors.affiliation: Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040, Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: María R
authors.initials: MR
authors.lastname: Pazos
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, via F. Muroni 23/A, 07100, Sassari, Italy.
authors.forename: Battistina
authors.initials: B
authors.lastname: Asproni
authors.affiliation: Department of Pharmacy, University of Genoa, Viale Benedetto XV n. 3, 16132, Genoa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cichero
authors.affiliation: Department of Pharmacy, University of Genoa, Viale Benedetto XV n. 3, 16132, Genoa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, via F. Muroni 23/A, 07100, Sassari, Italy.
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Pinna
authors.affiliation: Instituto de Química Médica, CSIC, Calle Juan de la Cierva, 3, 28006, Madrid, Spain.
authors.forename: Nadine
authors.initials: N
authors.lastname: Jagerovic
authors.affiliation: Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040, Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
authors.affiliation: Department of Chemistry and Pharmacy, University of Sassari, via F. Muroni 23/A, 07100, Sassari, Italy. Electronic address: muri@uniss.it.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Murineddu
mesh_terms: D063386:Cannabinoid Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D054314:Drug Inverse Agonism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D063386:Cannabinoid Receptor Agonists; D011724:Pyridazines; D043885:Receptor, Cannabinoid, CB2; D016244:Guanosine 5'-O-(3-Thiotriphosphate)
keywords: ADME model; CB(2) antagonism; Cannabinoid receptors; Docking studies; Scaffold hopping; Synthesis