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Title: L-Type calcium channel blockers: from diltiazem to 1,2,4-oxadiazol-5-ones via thiazinooxadiazol-3-one derivatives.
Authors: Budriesi, R
Cosimelli, B
Ioan, P
Ugenti, Mp
Carosati, E
Frosini, Maria
Fusi, Fabio 
Spisani, R
Saponara, Simona
Cruciani, G
Novellino, E
Spinelli, D
Chiarini, A.
Issue Date: 2009
Project: None 
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.
ISSN: 0022-2623
DOI: 10.1021/jm801351u
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