A new class of selective myocardial calcium channel modulators. 2. Role of the acetal chain in oxadiazol-3-one derivatives.
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.
Budriesi
Roberta
R
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Carosati
Emanuele
E
Chiarini
Alberto
A
Cosimelli
Barbara
B
Cruciani
Gabriele
G
Ioan
Pierfranco
P
Spinelli
Domenico
D
Spisani
Raffaella
R
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
D000080:Acetals; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D010069:Oxadiazoles