title: 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).
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Yiu
authors.forename: E E
authors.initials: EE
authors.lastname: Knaus
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004095:Dihydropyridines / Q000008:administration & dosage / Q000737:chemistry; D015736:Felodipine / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride
chemical_list: D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D011726:Pyridinium Compounds; D012965:Sodium Chloride; C038806:1,4-dihydropyridine; D015736:Felodipine