Budriesi Roberta, Carosati Emanuele, Chiarini Alberto, Cosimelli Barbara, Cruciani Gabriele, Ioan Pierfranco, Spinelli Domenico, Spisani Raffaella
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
J Med Chem. 2005 Apr 7;48(7):2445-56. doi: 10.1021/jm0493414.
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.
在本研究小组持续关注将8-芳基-8-羟基-8H-[1,4]噻嗪并[3,4-c][1,2,4]恶二唑-3-酮（1）用作钙通道阻滞剂的框架下，合成了多种缩醛并进行了“体外”测定。它们在结构上均与地尔硫卓和吡咯并苯并噻嗪有关。通过对多种缩醛残基进行功能测定来衡量对生物学特性的影响：饱和直链和支链、短和长的不饱和E和/或Z链以及苄基和甲基环己基残基。通过对活性最高的衍生物（5b）（EC(50) = 0.04 microM）进行选择性测定，该衍生物的活性比地尔硫卓（EC(50) = 0.79 microM）高20倍，排除了毒蕈碱或腺苷作用机制。获得了一个3D QSAR模型并用同源文献数据进行了验证，推导了未知结合位点的虚拟受体方案。以下药效团特征对效力有有利影响：一个带正电荷的中心、三个亲脂性基团和两个氢键受体基团。
