title: Tricyclic pyrazoles. Part 6. Benzofuro[3,2-c]pyrazole: a versatile architecture for CB2 selective ligands.
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.
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, SS, Italy. Electronic address: giopinna@uniss.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pinna
authors.affiliation: CNR, Istituto di Farmacologia Traslazionale, U.O.S. Cagliari, Edificio 5, Loc. Piscinamanna, 09010 Pula, CA, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Loriga
authors.affiliation: 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.
authors.forename: Paolo
authors.initials: P
authors.lastname: Lazzari
authors.affiliation: CNR, Istituto di Farmacologia Traslazionale, U.O.S. Cagliari, Edificio 5, Loc. Piscinamanna, 09010 Pula, CA, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ruiu
authors.affiliation: 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.
authors.forename: Matteo
authors.initials: M
authors.lastname: Falzoi
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, SS, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Frau
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, SS, Italy.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Pau
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, SS, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Murineddu
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, SS, Italy.
authors.forename: Battistina
authors.initials: B
authors.lastname: Asproni
authors.affiliation: Dipartimento di Chimica e Farmacia, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, SS, Italy. Electronic address: pinger@uniss.it.
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Pinna
mesh_terms: D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D008024:Ligands; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2
keywords: CB(2) agonists; CB(2) ligands; Cannabinoid receptors; Monoterpenes; benzofuro[3,2-c]pyrazole derivatives