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Eur J Med Chem. 2014 Jul 23;82:281-92. doi: 10.1016/j.ejmech.2014.05.055. Epub 2014 May 24.

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

Author information

1
Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, SS, Italy. Electronic address: giopinna@uniss.it.
2
CNR, Istituto di Farmacologia Traslazionale, U.O.S. Cagliari, Edificio 5, Loc. Piscinamanna, 09010 Pula, CA, Italy.
3
Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, SS, Italy; KemoTech Srl, Edificio 3, Loc. Piscinamanna, 09010 Pula, CA, Italy; PharmaNess Scarl, Edificio 5, Loc. Piscinamanna, 09010 Pula, CA, Italy. Electronic address: paolo.lazzari@kemotech.it.
4
Consorzio ELPRO, Edificio 5, Loc. Piscinamanna, 09010 Pula, CA, Italy; Dipartimento di Scienze della Vita e dell'Ambiente, Lab. Genetica, Università di Cagliari, Via T. Fiorelli 1, 09126 Cagliari, CA, Italy.
5
Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, SS, Italy.
6
Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, SS, Italy. Electronic address: pinger@uniss.it.

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 CB1 receptors, respectively. Preliminary functional assays evidenced CB2 agonism behaviour for all the assayed novel derivatives.

KEYWORDS:

CB(2) agonists; CB(2) ligands; Cannabinoid receptors; Monoterpenes; benzofuro[3,2-c]pyrazole derivatives

PMID:
24922543
DOI:
10.1016/j.ejmech.2014.05.055
[Indexed for MEDLINE]

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