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Tricyclic pyrazoles. Part 6: Benzofuro[3,2-c]pyrazole: A versatile architecture for CB2 selective ligands

Pinna, Giovanni and Loriga, Giovanni and Lazzari, Paolo and Ruiu, Stefania and Falzoi, Matteo and Frau, Simona and Pau, Amedeo and Murineddu, Gabriele and Asproni, Battistina and Pinna, Gérard Aimé (2014) Tricyclic pyrazoles. Part 6: Benzofuro[3,2-c]pyrazole: A versatile architecture for CB2 selective ligands. European Journal of Medicinal Chemistry, Vol. 82 , p. 281-292. ISSN 0223-5234. Article.

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DOI: 10.1016/j.ejmech.2014.05.055

Abstract

A new series of 1H-benzofuro[3,2-c]pyrazole-3-carboxamides was synthesized. The novel compounds (1524) 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 CB1 receptors, respectively.

Preliminary functional assays evidenced CB2 agonism behaviour for all the assayed novel derivatives.

Item Type:Article
ID Code:10008
Status:Published
Refereed:Yes
Uncontrolled Keywords:Cannabinoid receptors, CB2 ligands, benzofuro[3,2-c]pyrazole derivatives, monoterpenes, CB2 agonists
Subjects:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01-a Nuovi Dipartimenti dal 2012 > Chimica e Farmacia
Publisher:Elsevier Masson
ISSN:0223-5234
Deposited On:07 Aug 2014 09:07

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