Taylor M D, Badger E W, Steffen R P, Haleen S J, Pugsley T A, Shih Y H, Weishaar R E
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.
J Med Chem. 1988 Aug;31(8):1659-64. doi: 10.1021/jm00403a030.
The title compounds are novel double bond isomers of 1,4-dihydropyridine-type calcium channel blockers (CCB). These derivatives were prepared by using the Hantzsch dihydropyridine synthesis. The assignment of structure was based on spectroscopic data and a regiochemically unambiguous synthesis. Several of the analogues inhibited [3H]nitrendipine binding with IC50 values as low as 25 nM. By comparison, nifedipine, a clinically useful 1,4-dihydropyridine CCB, inhibits [3H]nitrendipine binding with an IC50 of 1.6 nM. In the Langendorff rat heart preparation, treatment with the more potent derivatives produced marked dose-related increases in coronary flow with little or no effect on heart rate or contractility, except at the highest concentrations tested. The selectivity for vascular versus cardiac effects was similar to that of nifedipine, i.e., the concentration producing vasodilation was approximately 2 orders of magnitude lower than the concentration eliciting cardiodepression. These novel isomers extend the structure-activity relationships for calcium channel blockers into a series closely related to the 1,4-dihydropyridines.
标题化合物是1,4 - 二氢吡啶类钙通道阻滞剂（CCB）的新型双键异构体。这些衍生物是通过汉茨希二氢吡啶合成法制备的。结构的确定基于光谱数据和区域化学明确的合成方法。几种类似物抑制[³H]尼群地平结合，IC50值低至25 nM。相比之下，临床上有用的1,4 - 二氢吡啶类CCB硝苯地平抑制[³H]尼群地平结合的IC50为1.6 nM。在离体大鼠心脏灌流实验中，用效力更强的衍生物处理后，冠状动脉血流量显著增加且呈剂量相关性，除了在测试的最高浓度下，对心率或心肌收缩力几乎没有影响。对血管与心脏作用的选择性与硝苯地平相似，即产生血管舒张的浓度比引起心脏抑制的浓度低约2个数量级。这些新型异构体将钙通道阻滞剂的构效关系扩展到了与1,4 - 二氢吡啶密切相关的一系列化合物中。
