Modification on the 1,2-dihydro-2-oxo-pyridine-3-carboxamide core to obtain multi-target modulators of endocannabinoid system

The endocannabinoid system dual-target ligand N-cycloheptyl-1,2-dihydro-5-bromo-1-(4-fluorobenzyl)-6-methyl-2-oxo-pyridine-3-carboxamide improves disease severity in a mouse model of multiple sclerosis

“…After that, cycloheptylamine was added and the reaction mixture was stirring at 0 C for 30 min and then at room temperature for 12 h to give the desired carboxamide derivative 1. Compound 1 was firstly treated with cesium carbonate in anhydrous DMF at room temperature for 1 h, and then with p-fluorobenzyl chloride, affording the desired N-alkylated derivative B1 together to the corresponding O-substituted derivative C1 in according to previously reported [24,25,32,33]. The two structural isomers were purified by flash chromatography.…”

“…Previously, our group reported the synthesis and biological evaluation of a series of compounds with general structure A (Fig. 1) which exhibited interesting multi-target profiles within the ECS [24]. In this work we developed a new class of compounds, B (Fig.…”

“…The modification of the general structure A was based on the observation that the phenyl ring at position 6 of the best compound of the series A (compound B1 in ref. 24) was predicted to be placed into a pocket of CB2R occupied by the phenyl ring of the antagonist AM10257, co-crystallized with CB2R (PDB code 5ZTY). This was consistent with the inverse agonist activity on CB2R observed for B1 [24].…”

“…24) was predicted to be placed into a pocket of CB2R occupied by the phenyl ring of the antagonist AM10257, co-crystallized with CB2R (PDB code 5ZTY). This was consistent with the inverse agonist activity on CB2R observed for B1 [24]. However, agonist compounds cocrystallized with CB1R with binding modes similar to AM10257 and B1 showed to leave the corresponding pocket unoccupied.…”

“…The new compounds are characterized by the presence of a pfluorobenzyl moiety at the N-1 position of the 1,2-dihydro-2-oxopyridine ring, a N-cycloheptyl carboxamide group at the 3-position and different substituents at position 5 (R) that were chosen on the basis of the best results obtained with the previous series [24,25,32,33]. Furthermore, the cycloheptyl ring of the carboxamide group (R2) was also substituted with a N-piperidinyl moiety or polyhydroxylated structures as carbohydrates.…”