jm0493414_si_001.pdf (112.14 kB)
A New Class of Selective Myocardial Calcium Channel Modulators. 2. Role of the Acetal Chain in Oxadiazol-3-one Derivatives
journal contribution
posted on 2005-04-07, 00:00 authored by Roberta Budriesi, Emanuele Carosati, Alberto Chiarini, Barbara Cosimelli, Gabriele Cruciani, Pierfranco Ioan, Domenico Spinelli, Raffaella SpisaniIn 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) (EC50 = 0.04 μM), which is 20 times more active
than diltiazem (EC50 = 0.79 μM), 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.