Atwal K S, Bergey J L, Hedberg A, Moreland S
J Med Chem. 1987 Apr;30(4):635-40. doi: 10.1021/jm00387a009.
2,5-Dihydro-4-methyl-2-phenyl-1,5-benzothiazepine-3-carboxylic acid esters, based on the structures of dihydropyridines and diltiazem, were synthesized from o-aminothiophenol and 2-(phenylmethylene)- 3-oxobutanoic acid esters. Biological evaluation in the potassium-depolarized rabbit aorta suggests that these compounds are calcium channel blockers. The in vitro activity was further confirmed by electrophysiological techniques. Structure-activity studies for the aromatic substitution showed that the 2-nitro derivative was the most potent (IC50 = 0.3 microM) compound in vitro while the ethyl ester was slightly better than the corresponding methyl ester. Replacement of sulfur with nitrogen atom provided 2,5-dihydro-4-methyl-2-(3-nitrophenyl)-1,5-benzodiazepine-3-carboxylic acid ethyl ester, which was only slightly less active than the corresponding benzothiazepine. Derivatization of the nitrogen in 2,5-dihydro-4-methyl- 2-(3-nitrophenyl)-1,5-benzothiazepine-3-carboxylic acid methyl ester with a (dimethylamino)ethyl group (present in diltiazem) provided 2,5-dihydro-5-[(dimethylamino)ethyl]- 4-methyl-2-(3-nitrophenyl)-1,5-benzo-thiazepine-3-carboxylic acid methyl ester, which was found to be equipotent to diltiazem in vitro. Radioligand binding studies using [3H]nitrendipine and [3H]diltiazem showed that the compound with the free nitrogen binds competitively into the dihydropyridine binding site while the molecule in which the nitrogen is alkylated with a (dimethylamino)ethyl group interacts competitively with both diltiazem and dihydropyridine binding sites. Our results therefore show that 2,5-dihydro-4-methyl-2-phenyl-1,5-benzothiazepine-3-carboxylic ester is a good starting point for designing dihydropyridine as well as diltiazem mimics.
基于二氢吡啶和地尔硫䓬的结构，由邻氨基硫酚和2-(苯基亚甲基)-3-氧代丁酸酯合成了2,5-二氢-4-甲基-2-苯基-1,5-苯并硫氮杂䓬-3-羧酸酯。在钾去极化兔主动脉中的生物学评价表明这些化合物是钙通道阻滞剂。电生理技术进一步证实了其体外活性。对芳香取代基的构效关系研究表明，2-硝基衍生物是体外活性最强的化合物（IC50 = 0.3 μM），而乙酯的活性略优于相应的甲酯。用氮原子取代硫原子得到2,5-二氢-4-甲基-2-(3-硝基苯基)-1,5-苯并二氮杂䓬-3-羧酸乙酯，其活性仅略低于相应的苯并硫氮杂䓬。用（二甲基氨基）乙基（存在于地尔硫䓬中）对2,5-二氢-4-甲基-2-(3-硝基苯基)-1,5-苯并硫氮杂䓬-3-羧酸甲酯中的氮进行衍生化，得到2,5-二氢-5-[(二甲基氨基)乙基]-4-甲基-2-(3-硝基苯基)-1,5-苯并硫氮杂䓬-3-羧酸甲酯，发现其在体外与地尔硫䓬活性相当。使用[3H]尼群地平和[3H]地尔硫䓬进行的放射性配体结合研究表明，具有游离氮的化合物竞争性地结合到二氢吡啶结合位点，而氮被（二甲基氨基）乙基烷基化的分子与地尔硫䓬和二氢吡啶结合位点都有竞争性相互作用。因此，我们的结果表明，2,5-二氢-4-甲基-2-苯基-1,5-苯并硫氮杂䓬-3-羧酸酯是设计二氢吡啶以及地尔硫䓬类似物的良好起始点。
