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

Abstract

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 × 10‐9M) was about 44‐fold more active as a calcium channel antagonist than the reference drug nimodipine (IC50 = 1.49 × 10‐8M), but 4‐fold less potent than felodipine (IC50 = 1.45 × 10‐9M). Compound 16, possessing the 1‐methyl‐3‐pyridylcarbonyloxy chemical delivery system moiety is a slightly less potent calcium channel antagonist (IC50 = 2.99 × 10‐8M) 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.

A Number of Marketed Dihydropyridine Calcium Channel Blockers Have Mineralocorticoid Receptor Antagonist Activity

“…The main antihypertensive action, however, is still without question via blockade of the L-type calcium channels, where their potency is normally in the 1 to 10 nmol/L range. 13,14 In contrast, the lowest MR IC50 is still above 100 nmol/L. Only when high doses are used or if compound accumulates in particular tissues can there be substantial effect on MR.…”

Lipophilic 2-(4-chlorophenyl)-4-thiazolyl-1,4-dihydropyridines: synthesis, calcium channel antagonist activity, and protection against pentylenetetrazole-induced seizure

“…In addition it has been shown that lipophilic 4-(2,3-dichlorophenyl) or 4-imidazolyl-1,4-dihydropyridines have anticonvulsant activity (Yiu and Knaus, 1999;Navidpour et al, 2004).…”

Solubilities of Some Cyclohexyl Derivatives of Dialkyl 1,4-Dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-imidazol-2-yl)- 3,5-pyridinedicarboxylates (Nifedipine Analogues) in Supercritical Carbon Dioxide. Part I

“…Very recently, Knuas and co-workers have synthesized new generations of DHP derivatives in which the phenyl substituent at the C-4 position of the DHP ring has been replaced by other aromatic substituents such as imidazolyl and pyridine. [8][9][10][11][12] Recently, some new derivatives of DHP containing a 1-methyl-5-nitro-imidazol-2-yl substituent at the C-4 position and different ester substituents on the C-3 and C-5 positions of the DHP ring have been synthesized. [12][13][14][15][16] The calcium channel antagonist activity of the compounds in Guinea-pig Ileal was determined, and it was found that the activity of some derivatives was higher than that of nifedipine.…”

“…Some derivatives such as nifedipine, nicardipine, amlodipine, and nitrendipine are now commercially available in drug stores. Very recently, Knuas and co-workers have synthesized new generations of DHP derivatives in which the phenyl substituent at the C-4 position of the DHP ring has been replaced by other aromatic substituents such as imidazolyl and pyridine. − Recently, some new derivatives of DHP containing a 1-methyl-5-nitro-imidazol-2-yl substituent at the C-4 position and different ester substituents on the C-3 and C-5 positions of the DHP ring have been synthesized. − The calcium channel antagonist activity of the compounds in Guinea-pig Ileal was determined, and it was found that the activity of some derivatives was higher than that of nifedipine. − Earlier, we carried out some quantitative structure−activity relationship analysis on these compounds − and found that lipophilicity and steric and electronic properties are the major factors controlling the binding of these molecules to their receptor.…”