2014 May 24;82C:281-292. doi: 10.1016/j.ejmech.2014.05.055. [Epub ahead of print]
Tricyclic pyrazoles. Part 6. Benzofuro[3,2-c]pyrazole: A versatile architecture for CB2 selective ligands.
Pinna G1, Loriga G2, Lazzari P3, Ruiu S2, Falzoi M4, Frau S5, Pau A5, Murineddu G5, Asproni B5, Pinna GA6.
Abstract
A new series of 1H-benzofuro[3,2-c]pyrazole-3-carboxamides was synthesized. The novel compounds (15-24) were evaluated for their affinity to CB2 and CB1 cannabinoid receptors. The synthesis of the title compounds takes advantage of the acid-catalysed thermal cyclization of bicyclic hydrazone ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)-2-(6-methyl-3-oxo-2,3-dihydrobenzofuran-2-yl)acetate to tricyclic ethyl 1-(2,4-dichlorophenyl)-6-methyl-1H-benzofuro[3,2-c]pyrazol-3-carboxylate. All the obtained derivatives showed high affinity to CB2 receptors. Moreover, significant selectivity for CB2 over CB1 receptors was highlighted for lead derivatives amongst the novel series. The best binding profiles were determined for homologues bearing monocyclic and bicyclic monoterpenic substituents at the carbamoyl group at 3 position of the pyrazole ring (KiCB2 < 4 nM). In particular, the isopinocampheyl-substituted derivative 22 exhibited the highest selectivity for CB2 receptors with Ki values of 3.7 and 2398 nM for CB2 and CB1receptors, respectively. Preliminary functional assays evidenced CB2 agonism behaviour for all the assayed novel derivatives.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
CB(2) agonists; CB(2) ligands; Cannabinoid receptors; Monoterpenes; benzofuro[3,2-c]pyrazole derivatives
- PMID:
24922543
[PubMed – as supplied by publisher]
