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.
3-Ethyl 5-methyl 1,4-dihydro-2-[(2-hydroxyethoxy) methyl]-6-methyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate (13), a bioisostere of amlodipine, was prepared by the reaction of ethyl 4-(2-hydroxyethoxy)acetoacetate (11) with methyl 2-(2,3-dichlorobenzylidene)acetoacetate (12) and NH4OAc. Compound 13 was elaborated to the target product 3-ethyl 5-methyl 1,4-dihydro-2-[2- [(1-methyl-1,4-dihydropyridyl-3-carbonyloxy)ethoxy]methyl]- 6-methyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate (16). The C-2 CH2OCH2CH2OH compound (13, IC50 = 6.56 x 10(-9) M) was about 44-fold more active as a calcium channel antagonist than the reference drug nimodipine (IC50 = 1.49 x 10(-8) M), but 4-fold less potent than felodipine (IC50 = 1.45 x 10(-9) M). Compound 16, possessing the 1-methyl-3-pyridylcarbonyloxy chemical delivery system moiety is a slightly less potent calcium channel antagonist (IC50 = 2.99 x 10(-8) M) than the parent compound 13. Compounds 13, 16, felodipine and nimodipine are highly lipophilic (Kp = 227, 344, 442 and 187, respectively). The C-2 CH2OCH2CH2OH compound (13) exhibited equipotent anticonvulsant activity to nimodipine in the maximal electroshock (MES) anticonvulsant screen. Unlike nimodipine, 13 provided modest protection in the subcutaneous metrazol (scMet) anticonvulsant screen. In contrast, compound 16 was inactive in both the MES and scMet screens.
Yiu
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Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Knaus
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D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015736:Felodipine / Q000493:pharmacokinetics / Q000494:pharmacology; D006168:Guinea Pigs; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects; D009553:Nimodipine / Q000493:pharmacokinetics / Q000494:pharmacology
D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D009553:Nimodipine; C038806:1,4-dihydropyridine; D015736:Felodipine