Yiu S, Knaus E E
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
J Med Chem. 1996 Nov 8;39(23):4576-82. doi: 10.1021/jm960531r.
3-(2-Hydroxyethyl) 5-methyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-pyridinedi-carboxyla te (7) was prepared using a modified Hantzsch reaction, which was then elaborated to 3-[2-[[(1-methyl-1,4-dihydropyrid-3-yl)carbonyl]oxy]ethyl]5-methyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylat e [10, felodipine-chemical delivery system (CDS)]. The equipotent 3-(2-hydroxyethyl) 7 (IC50 = 3.04 x 10(-8) M) and felodipine-CDS (10, IC50 = 3.10 x 10(-8) M) were, respectively, 2- and 21-fold less potent calcium channel antagonists than the reference drugs nimodipine (IC50 = 1.49 x 10(-8) M) and felodipine (IC50 = 1.45 x 10(-9) M). Compounds 7, 10, nimodipine, and felodipine are highly lipophilic (Kp = 236, 366, 187, and 442, respectively). 3-(2-Hydroxyethyl) 7, felodipine-CDS (10), and felodipine provided protection against maximal electroshock-induced seizures in mice but were inactive in the subcutaneous metrazol anticonvulsant screen. In vitro incubation studies of felodipine with rat plasma and 20% brain homogenates showed felodipine was very stable in both biological media. Similar incubations of felodipine-CDS showed its rate of biotransformation followed psuedo-first-order kinetics with half-lives of 15.5 h in rat plasma and 1.3 h in 20% rat brain homgenates. In vivo biodistribution of felodipine and felodipine-CDS was studied. Uptake of felodipine in brain produced a peak brain concentration of 5 micrograms/g of brain tissue at 5 min, after which it rapidly egressed from brain resulting in undetectable levels at 60 min. Peak blood concentrations of 10 occurred at about 7 min followed by a rapid decline to a near undetectable concentration by 17 min. The pyridinium salt species 9, resulting from oxidation of 10, also reached peak concentrations at about 7 min but it slowly decreased to undetectable concentrations at 2 h. 3-(2-Hydroxyethyl) 7 remained at near undetectable concentrations throughout a 2 h time period. Localization of 10 in brain provided a peak concentration of 4.2 micrograms/g of brain tissue at 5 min and then decreased to negligible concentrations at 15 min. The concentration of oxidized pyridinium species 9 in brain remained high providing detectable concentrations up to 4 days. In contrast, the concentration of the 3-(2-hydroxyethyl) hydrolysis product 7 in brain remained at very low levels throughout the study. The slow hydrolysis rate of the pyridinium ester 9 to the 3-(2-hydroxyethyl) 7 and the rapid egression of felodipine-CDS from brain are believed to contribute to the moderate anticonvulsant activity exhibited hy the felodipine-CDS (10).
3-(2-羟乙基)5-甲基-1,4-二氢-2,6-二甲基-4-(2,3-二氯苯基)-3,5-吡啶二甲酸酯(7)采用改良的汉茨希反应制备，然后将其进一步制备为3-[2-[[(1-甲基-1,4-二氢吡啶-3-基)羰基]氧基]乙基]5-甲基-1,4-二氢-2,6-二甲基-4-(2,3-二氯苯基)-3,5-吡啶二甲酸酯[10，非洛地平化学传递系统(CDS)]。等效的3-(2-羟乙基)7(IC50 = 3.04×10⁻⁸ M)和非洛地平-CDS(10，IC50 = 3.10×10⁻⁸ M)作为钙通道拮抗剂，其效力分别比参比药物尼莫地平(IC50 = 1.49×10⁻⁸ M)和非洛地平(IC50 = 1.45×10⁻⁹ M)低2倍和21倍。化合物7、10、尼莫地平和非洛地平具有高度亲脂性(分配系数Kp分别为236、366、187和442)。3-(2-羟乙基)7、非洛地平-CDS(10)和非洛地平可保护小鼠免受最大电休克诱导的惊厥，但在皮下戊四氮抗惊厥筛选中无活性。非洛地平与大鼠血浆和20%脑匀浆的体外孵育研究表明，非洛地平在两种生物介质中都非常稳定。非洛地平-CDS的类似孵育表明，其生物转化速率符合伪一级动力学，在大鼠血浆中的半衰期为15.5小时，在20%大鼠脑匀浆中的半衰期为1.3小时。研究了非洛地平和非洛地平-CDS的体内生物分布。非洛地平在脑中的摄取在5分钟时产生脑组织浓度峰值为5微克/克，之后它迅速从脑中排出，在60分钟时降至检测不到的水平。10的血药浓度峰值出现在约7分钟，随后迅速下降，到17分钟时降至几乎检测不到的浓度。由10氧化产生的吡啶盐类9在约7分钟时也达到峰值浓度，但在2小时时缓慢降至检测不到的浓度。在整个2小时时间段内，3-(2-羟乙基)保持在几乎检测不到的浓度。10在脑中的定位在5分钟时产生脑组织浓度峰值为4.2微克/克，然后在15分钟时降至可忽略不计的浓度。脑中氧化吡啶类9的浓度一直很高，在长达4天的时间内都可检测到。相比之下，在整个研究过程中，脑中3-(2-羟乙基)水解产物7的浓度一直保持在非常低的水平。吡啶酯9缓慢水解为3-(2-羟乙基)7以及非洛地平-CDS迅速从脑中排出，被认为是导致非洛地平-CDS(10)表现出中等抗惊厥活性的原因。
