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

  • Eur J Med Chem. 2017 Feb 15:127:398-412. doi: 10.1016/j.ejmech.2017.01.002.
Giulio Ragusa  1 ,  María Gómez-Cañas  2 ,  Paula Morales  3 ,  Carmen Rodríguez-Cueto  2 ,  María R Pazos  2 ,  Battistina Asproni  1 ,  Elena Cichero  4 ,  Paola Fossa  4 ,  Gerard A Pinna  1 ,  Nadine Jagerovic  3 ,  Javier Fernández-Ruiz  2 ,  Gabriele Murineddu  5
Affiliations
  • 1. Department of Chemistry and Pharmacy, University of Sassari, via F. Muroni 23/A, 07100, Sassari, Italy.
  • 2. 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.
  • 3. Instituto de Química Médica, CSIC, Calle Juan de la Cierva, 3, 28006, Madrid, Spain.
  • 4. Department of Pharmacy, University of Genoa, Viale Benedetto XV n. 3, 16132, Genoa, Italy.
  • 5. Department of Chemistry and Pharmacy, University of Sassari, via F. Muroni 23/A, 07100, Sassari, Italy. Electronic address: [email protected].
PMID: 28088085 DOI: 10.1016/j.ejmech.2017.01.002
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.

Keywords
ADME model; CB(2) antagonism; Cannabinoid receptors; Docking studies; Scaffold hopping; Synthesis.