title: A new class of selective myocardial calcium channel modulators. 2. Role of the acetal chain in oxadiazol-3-one derivatives.
abstract: In the framework of the continuing interest of this research group in the use of 8-aryl-8-hydroxy-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (1) as calcium entry blockers, a number of acetals were synthesized and assayed "in vitro". All of them are structurally related to diltiazem and pyrrolobenzothiazines. The effect on the biological profile was measured by functional assays for a wide variety of acetal residues: saturated linear and branched chains, short and long unsaturated E and/or Z chains as well as benzyl and methylcyclohexyl residues. From selective assays on the most active derivative (5b) (EC(50) = 0.04 microM), which is 20 times more active than diltiazem (EC(50) = 0.79 microM), a muscarinic or adenosinic mechanism of action was excluded. A 3D QSAR model was obtained and validated with homologous literature data, and a virtual receptor scheme was derived for the unknown binding site. The following pharmacophoric features favorably affect the potency: one positively charged center, three lipophilic groups, and two hydrogen-bonding acceptor groups.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Budriesi
authors.forename: Emanuele
authors.initials: E
authors.lastname: Carosati
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarini
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Ioan
authors.forename: Domenico
authors.initials: D
authors.lastname: Spinelli
authors.forename: Raffaella
authors.initials: R
authors.lastname: Spisani
mesh_terms: D000080:Acetals / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000502:physiology; D003864:Depression, Chemical; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008958:Models, Molecular; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000080:Acetals; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D010069:Oxadiazoles