title: Tricyclic pyrazoles part 7. Discovery of potent and selective dihydrothienocyclopentapyrazole derived CB2 ligands.
abstract: A series of dihydrothienocyclopentapyrazole-based derivatives was synthesized and evaluated for the affinity at CB1 and CB2 receptors. The major term, the 6-methyl-1-(1,4-dichlorophenyl)-N-piperidinyl)-1,4-dihydrothieno[2',3'-4,5]cyclopenta[1,2-c]pyrazole-3-carboxamide (6a), displayed a high affinity and good selectivity for CB2 receptors (Ki values of 2.30 nM for CB2 receptor and 440 nM for CB1 receptors respectively). Subsequent analogue preparation resulted in the identification of compounds such as 6b, 6d, 6e, 6k, 6l, 6m, 6s and 6t that showed 1.3-485 fold selectivity for CB2 receptors with potencies in the 1.1-7.2 nM range. These compounds profiled as full agonists at CB2 receptor in an inhibition assay of P-ERK 1/2 up regulation in HL-60 cells.
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy. Electronic address: gsvpinna@gmail.com.
authors.forename: Giansalvo
authors.initials: G
authors.lastname: Pinna
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Maria Michela
authors.initials: MM
authors.lastname: Curzu
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Dore
authors.affiliation: PharmaNess S.c.a r.l., Edificio 5, Località Piscinamanna, 09010 Pula, CA, Italy; KemoTech Srl, Edificio 3, Loc. Piscinamanna, 09010 Pula, CA, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Lazzari
authors.affiliation: CNR, Istituto di Farmacologia Traslazionale, UOS di Cagliari, Edificio 5, Località Piscinamanna, 09010 Pula, CA, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ruiu
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Pau
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Murineddu
authors.affiliation: Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy.
authors.forename: Gérard A
authors.initials: GA
authors.lastname: Pinna
mesh_terms: D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D008024:Ligands; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; C031280:pyrazole
keywords: Amides; CB2 agonists; Cannabinoid receptors; Dihydrothienocyclopentapyrazole; Thiophene tricycles