title: L-Type calcium channel blockers: from diltiazem to 1,2,4-oxadiazol-5-ones via thiazinooxadiazol-3-one derivatives.
abstract: The research of compounds with L-type calcium channels (LTCCs) blocking activity continued with heterocyclic compounds containing the 1,2,4-oxadiazol-5-one ring. For a series of 22 new derivatives of 3-aryl-4[(Z)-(1-methyl-2-alkylsulphanyl-vinyl)][1,2,4]oxadiazol-5(4H)-ones, which represent the "frozen" open chain counterpart of the cyclic aryl-thiazinooxadiazolones previously examined, we report here the synthesis and the characterization as LTCC blockers, evaluated on isolated tissues of guinea pig. The most interesting compound, 8b, was tested also on L-type calcium current recorded in isolated rat tail artery myocytes. Overall, six compounds were more potent than diltiazem, and binding assays confirmed the direct interaction with the benzothiazepine binding site. As the cyclic aryl-thiazinooxadiazolones, p-bromine substituted compounds were generally more potent than the corresponding p-chlorine ones. A saturated or unsaturated alkyl chain or a bulky group at the sulfur atom were detrimental to the potency, while the compounds with S-methyl groups, i.e., thioether (8b), sulfoxide (16a,b), and sulfone (17b), gave the best results.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Bologna, Via Belmeloro 6, 40126 Bologna, Italy. roberta.budriesi@unibo.it
authors.forename: Roberta
authors.initials: R
authors.lastname: Budriesi
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Ioan
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Ugenti
authors.forename: Emanuele
authors.initials: E
authors.lastname: Carosati
authors.forename: Maria
authors.initials: M
authors.lastname: Frosini
authors.forename: Fabio
authors.initials: F
authors.lastname: Fusi
authors.forename: Raffaella
authors.initials: R
authors.lastname: Spisani
authors.forename: Simona
authors.initials: S
authors.lastname: Saponara
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Domenico
authors.initials: D
authors.lastname: Spinelli
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarini