33736-01-5Relevant articles and documents
Synthesis, biological evaluation, calcium channel antagonist activity, and anticonvulsant activity of felodipine coupled to a dihydropyridine- pyridinium salt redox chemical delivery system
Yiu, Sai-Hay,Knaus, Edward E.
, p. 4576 - 4582 (1996)
3-(2-Hydroxyethyl) 5-methyl 1,4-dihydro-2,6-dimethyl-4-(2,3- dichlorophenyl)-3,5-pyridinedicarboxylate (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-pyridinedicarboxylate [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 (K(p) = 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 homogenates. In vivo biodistribution of felodipine and felodipine-CDS was studied. Uptake of felodipine in brain produced a peak brain concentration of 5 μg/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 μg/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 by the felodipine-CDS (10).
Rapid and simple method of monoacylation of polyols by β-ketoesters using microwave irradiation
Karmee, Sanjib Kumar,Chadha, Anju
, p. 1151 - 1160 (2005)
Polyols undergo rapid selective transesterification with β-ketoesters upon microwave irradiation in solvent-free and catalyst-free conditions to form monoesters. Copyright Taylor & Francis, Inc.
Dihydropyridines as inhibitors of capacitative calcium entry in leukemic HL-60 cells
Harper, Jacquie L.,Camerini-Otero, Carol S.,Li, An-Hu,Kim, Soon-Ai,Jacobson, Kenneth A.,Daly, John W.
, p. 329 - 338 (2007/10/03)
A series of 1,4-dihydropyridines (DHPs) were investigated as inhibitors of capacitative calcium influx through store-operated calcium (SOC) channels. Such channels activate after ATP-elicited release of inositol trisphosphate (IP3)-sensitive calcium stores in leukemia HL-60 cells. The most potent DHPs were those containing a 4-phenyl group with an electron-withdrawing substituent, such as m- or p-nitro- or m-trifluoromethyl (IC50 values: 3-6μM). Benzyl esters, corresponding to the usual ethyl/methyl esters of the DHPs developed as L-type calcium channel blockers, retained potency at SOC channels, as did N-substituted DHPs. N-Methylation reduced by orders of magnitude the potency at L-type channels resulting in DHPs nearly equipotent at SOC and L-type channels. DHPs with N-ethyl, N-allyl, and N-propargyl groups also had similar potencies at SOC and L-type channels. Replacement of the usual 6-methyl group of DHPs with larger groups, such as cyclobutyl or phenyl, eliminated activity at the SOC channels; such DHPs instead elicited formation of inositol phosphates and release of IP3-sensitive calcium stores. Other DHPs also caused a release of calcium stores, but usually at significantly higher concentrations than those required for the inhibition of capacitative calcium influx. Certain DHPs appeared to cause an incomplete blockade of SOC channel-dependent elevations of calcium, suggesting the presence of more than one class of such channels in HL-60 cells. N-Methylnitrendipine (IC50 2.6μM, MRS 1844) and N-propargylnifrendipine (IC50 1.7μM, MRS 1845) represent possible lead compounds for the development of selective SOC channel inhibitors.
