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Papers of the Week

2022 Dec 06

Pharmaceuticals (Basel)



2-Arylpropionic Acid Pyrazolamides as Cannabinoid CB2 Receptor Inverse Agonists Endowed with Anti-Inflammatory Properties.


de Oliveira DR, Maia RC, de Carvalho França PR, Fernandes PD, Barbosa G, Lima LM, Fraga C MA
Pharmaceuticals (Basel). 2022 Dec 06; 15(12).
PMID: 36558970.


Among the most recent proposals regarding the mechanism of action of dipyrone, the modulation of cannabinoid receptors CB and CB appears to be a promising hypothesis. In this context, the present work describes a series of five novel pyrazolamides (-) designed as molecular hybrids of dipyrone metabolites and NSAIDs, such as ibuprofen and flurbiprofen. Target compounds were obtained in good overall yields (50-80%) by classical amide coupling between 4-aminoantipyrine and arylacetic or arylpropionic acids, followed in some cases by -methylation of the amide group. The compounds presented good physicochemical properties in addition to stability to chemical (pH 2 and 7.4) and enzymatic (plasma esterases) hydrolysis and showed medium to high gastrointestinal and BBB permeabilities in the PAMPA assay. When subjected to functional testing on CB- or CB-transfected cells, compounds demonstrated an inverse agonist profile on CB receptors and the further characterization of compound LASSBio-2265 () revealed moderate binding affinity to CB receptor (K = 16 µM) with an EC = 0.36 µM (E = 63%). LASSBio-2265 () (at 1, 3, and 10 mg/kg p.o.) was investigated in the formalin test in mice and a remarkable analgesic activity in the late inflammatory phase was observed, suggesting it could be promising for the treatment of pain syndromes associated with chronic inflammatory diseases.