Synthesis, Biological Evaluation, Calcium Channel Antagonist Activity, and Anticonvulsant Activity of Felodipine Coupled to a Dihydropyridine−Pyridinium Salt Redox Chemical Delivery System

Abstract

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).

Pharmacology of L-type Calcium Channels: Novel Drugs for Old Targets?

“…Brain drug delivery approaches are available [113, 114]. One such approach, using a chemical delivery system (CDS), has already been applied to increase brain concentrations of the widely used DHP felodipine [115]. Bodor’s lipophilic [(1-methyl-1,4-dihydropyrid-3-yl)-carbonyl]oxy (amino) acts as a chemical delivery system that, after entry into brain is oxidized to a polar pyridinium species.…”

Targeting drugs to the brain by redox chemical delivery systems

“…The antiseizure potency of a CDS for felodipidine (72) was studied by Yiu and Knaus. 248 In vitro investigations revealed that, while the parent drug is very stable in biological media, biotransformations of the CDS (73, Fig. 29) showed a pseudo-®rst-order kinetics with t 1/2 of 15.5 h in rat plasma and 1.3 h in 20% rat brain homogenate.…”

Synthesis, Calcium Channel Antagonist Activity, and Anticonvulsant Activity of 3-Ethyl 5-Methyl 1,4-Dihydro-2-[(2-hydroxyethoxy)methyl]-6-methyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate Coupled to a 1-Methyl-1,4-dihydropyridyl-3-carbonyl Chemical Delivery System

“…Accordingly, coupling this CDS to a γ-aminobutyric acid derivative (GABA-CDS, 3) [8] , or diphenylhydantoin (DPH-CDS, 4) [9] , resulted in superior anticonvulsant protection in animal seizure models compared to the parent compounds GABA or DPH. In an earlier study, it was shown that the C-3 2-hydroxyethyl analog of felodipine (5) and the felodipine-CDS (6) provided protection against maximal electroshock (MES) induced seizures in mice but were inactive in the subcutaneous metrazol (scMet) anticonvulsant screen [10] . The felodipine-CDS (6) enters the brain readily, and it undergoes facile oxidation to a pyridinium species that is retained in brain tissues up to four days after drug administration.…”

“…The felodipine-CDS (6) enters the brain readily, and it undergoes facile oxidation to a pyridinium species that is retained in brain tissues up to four days after drug administration. However, the slow hydrolysis rate of the pyridinium ester to the 3-(2-hydroxyethyl) compound 5 and the rapid egression of felodipine-CDS (6) from brain likely contributed to the modest anticonvulsant activity exhibited by the felodpine-CDS (6) [10] . The long acting second-generation CCA amlodipine (7), having a novel C-2 -CH2OCH2CH2NH2 substituent, is a potent antihypertensive drug that is amenable to once-a-day dosing [11] .…”