L-Type Calcium Channel Blockers: From Diltiazem to 1,2,4-Oxadiazol-5-ones via Thiazinooxadiazol-3-one Derivatives

详细信息    查看全文

• 作者：Roberta Budriesi ; Barbara Cosimelli ; Pierfranco Ioan ; Maria Paola Ugenti ; Emanuele Carosati ; Maria Frosini ; Fabio Fusi ; Raffaella Spisani ; Simona Saponara ; Gabriele Cruciani ; Ettore Novellino ; Domenic
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：April 23, 2009
• 年：2009
• 卷：52
• 期：8
• 页码：2352-2362
• 全文大小：328K
• 年卷期：v.52,no.8(April 23, 2009)
• ISSN：1520-4804

文摘

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.