Synthesis and calcium channel antagonist activity of dialkyl 1,4-dihydro-2,6-dimethyl-4-(pyridinyl)-3,5-pyridinedicarboxylates

Abstract

The Hantzsch condensation of alkyl acetoacetates 3 with methyl 3-aminocrotonate (4) and pyridinecarboxaldehydes 5 afforded the unsymmetrical alkyl methyl 1,4-dihydro-2,6-dimethyl-4-(pyridinyl)-3,5-pyridinedicarboxylates 6, whereas condensation of 3 with 5 and ammonium hydroxide gave the symmetrical dialkyl 1,4-dihydro-2,6-dimethyl-4-(pyridinyl)-3,5-pyridinedicarboxylates 7. The calcium channel antagonist activities of disubstituted 1,4-dihydro-3,5-pyridinedicarboxylates 6,7, and 9 were determined with use of the muscarinic-receptor-mediated Ca2+-dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative potency order for isomeric pyridinyl analogues 6 and 7 was 2-pyridinyl greater than 3-pyridinyl greater than 4-pyridinyl. Increasing the size of the alkyl ester substituents enhanced activity. Compounds having nonidentical ester substituents were more potent than those having identical ester substituents. Replacement of the C-3 and/or C-5 ester substituent(s) by a cyano substituent(s) decreased activity significantly. An approximate 1:1 correlation between the IC50 value for inhibition of [3H]nitrendipine binding and inhibition of the tonic component of the muscarinic-induced contractile response was observed. The test results suggest that a 4-(pyridinyl) substituent is bioisosteric with a 4-(nitrophenyl) substituent on a 1,4-dihydropyridine ring system where o-, m-, and p-nitrophenyl are bioisosteric with 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl, respectively.

Synthesis and Calcium Channel Antagonist Activity of Dialkyl 1,4-Dihydro-2,6-dimethyl-4-[4-(1-methoxycarbonyl-1,4-dihydropyridyl)]-3,5- pyridinedicarboxylates

“…Changes in the substitution pattern at the C-3, C-4, and C-5 positions of nifedipine alter potency [2,10,11] and the conformation [16,17] of the 1,4-dihydropyridine ring. Strain due to non-bonded interactions between the C-3, C-4, and C-5 substituents is relieved primarily by increasing the planarity (flatness) of the 1,4-dihydropyridine ring and distortion of the bond angle about C-4, which is associated with increased calcium channel antagonist activity [2,16] .…”

“…The ene portion of the C-4 1-methoxycarbonyl-1,4-dihydropyridine moiety is expected to be planar, whereas there will be considerable distortion from planarity at its C-4 and N-1 positions. It was anticipated that the N-CO 2 Me substituent could exhibit a steric effect similar to a 4-nitro substituent on a phenyl ring, or the free electron-pair on a 4-pyridyl substituent [11] . These topological differences, present in the C-4 1-methoxycarbonyl-1,4-dihydropyridyl substituent, could influence its interaction with the 1,4-dihydropyridine binding site.…”

“…In a previous study, we reported [11] that a C-4 2-, 3-, or 4-pyridyl substituent is bioisosteric with a 2-, 3-, or 4-nitrophenyl substituent for dialkyl 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates (2). The subsequent elaboration of the 4-(3-pyridyl) compounds (2) to the respective 4-{3-[1-alkoxy(phenoxy)carbonyl-1,2-(and 1,6-)dihydropyridyl]} compounds (3)(4) [18,19] , or the C-4 3-(1-methoxycarbonyl-4-substituted-1,4-dihydropyridyl) analogs (5) [20] , indicated that compounds 3-5 are bioisosteric to a C-4 3-nitrophenyl or a 3-pyridyl substituent in classical 1,4-dihydropyridine calcium channel antagonists.…”

“…A quantitative structure-activity relationship study indicated that the potency of nifedipine analogs was dependent upon lipophilicity, an electronic term, and separate terms for each position on the aromatic ring [9] . Changes in the substitution pattern at the C-3, C-4, and C-5 positions of nifedipine alter potency [2,10,11] , tissue selectivity [12][13][14][15] , and the conformation [16,17] of the 1,4-dihydropyridine ring.…”

Specific inhibition of Ca‐activated K channels in red cells by selected dihydropyridine derivatives

“…Ouabain, nifedipine and bumetanide were from Sigma Chemical Co. Nitrendipine was a gift from Bayer. The 1,4-dihydropyridyl derivatives (1-32) were prepared using the literature procedures as follows: 8-10, 16 (Dagnino et al, 1986);1-5, 18, 20, 22 (Akula et al, 1989);26-27, 29, 31-32 (Wynn et al, 1988);6, 11-13 (Akula et al, 1990a);7, 14 (Akula et al, 1990b); 19, 21 (Ramesh et al, 1987);15, 17, 23-25, 28, 30 inhibitors of the Ca-activated K+ efflux from normal (HbAA) red cells. Molecules 26, 29, 32 were then selected for detailed study, and dose-response curves generated for inhibition of both the red cell Gardos-channel, and an ileal smooth muscle preparation.…”