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

The sodium borohydride reduction of 3,5-disubstituted 1,4-dihydro-2,6-dimethyl-4-(pyridinyl)pyridines 2 and 5 in the presence of methyl, phenyl, or tert-butyl chloroformate afforded the respective 4-(dihydropyridinyl)-1,4-dihydropyridines 4 and 6 in good yield. Products 4 comprised a mixture of the 1,2- and 1,6-dihydropyridinyl regioisomers 4a and 4b where 4a was always the predominant regioisomer. Compounds possessing a 4-[dihydro-1-(phenoxycarbonyl)-3-pyridinyl] substituent, such as 26, were also a mixture of two regioisomers 26a and 26b, and each regioisomer existed as a mixture of two rotamers in Me2SO-d6 at 25 degrees C (26a', 26a'', and 26b', 26b'') due to restricted rotation about the nitrogen-to-carbonyl carbamate bond. The calcium antagonist activities for 4 and 6 were determined by using the muscarinic receptor-mediated Ca2+-dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative order of activities for the 4-(dihydropyridinyl) analogues was 4-(dihydro-3-pyridinyl) greater than 4-(dihydro-4-pyridinyl). Increasing the size of the C-3(5) alkyl ester substituents increased activity. Compounds having nonidentical ester substituents were more active than those having identical ester substituents. Replacement of the C-3 and/or C-5 ester substituents 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-(dihydropyridinyl) substituent is bioisosteric with a 4-(nitrophenyl) substituent on a 1,4-dihydropyridine ring where m- and p-nitrophenyl are bioisosteric with the 4-[1,2(1,6)-dihydro-3-pyridinyl] 4 and 4-(1,2-dihydro-4-pyridinyl) 6 isomers, respectively.

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

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-modulating effects of alkyl (or cycloalkyl) 1,4-dihydro-2,6-dimethyl-3-nitro-4-pyridyl-5-pyridinecarboxylate racemates and enantiomers.

A group of racemic alkyl (or cycloalkyl) 1,4-dihydro-2,6- dimethyl-3-nitro-4-(2-, 3-, or 4-pyridyl)-5-pyridinecarboxylate isomers (6-14) were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with an alkyl (or cycloalkyl) 3-aminocrotonate and 2-, 3-, or 4-pyridinecarboxaldehyde. Determination of their in vitro calcium channel-modulating activities using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays showed that the 2-pyridyl isomers acted as dual cardioselective calcium channel agonists (GPLA)/smooth muscle selective calcium channel antagonists (GPILSM). In contrast, the 3-pyridyl and 4-pyridyl isomers acted as calcium channel agonists on both GPLA and GPILSM. In the C-4 2-pyridyl group of compounds, the size of the C-5 alkyl (or cycloalkyl) ester substituent was a determinant of GPILSM antagonist activity where the relative activity profile was cyclopentyl and cyclohexyl > t-Bu, i-Bu, and Et > MeOCH2CH2 > Me. The point of attachment of the C-4 pyridyl substituent was a determinant of GPLA agonist activity where the potency order was generally 4- and 3-pyridyl > 2-pyridyl. (+)-Cyclohexyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-pyridyl)-5- pyridinecarboxylate [(+)-14a] was a less potent calcium antagonist (IC50 = 5.27 x 10(-6) M) than the (-)-enantiomer (IC50 = 7.48 x 10(-8) M) on GPILSM. In the GPLA assay, (+)-14a exhibited a much more potent agonist effect (EC50 = 8.45 x 10(-6) M) relative to the marginal agonist effect produced by (-)-14a. The C-4 2-pyridyl compounds (enantiomers) constitute a novel type of 1,4-dihydropyridine calcium channel modulator that could provide a new drug design concept directed toward the treatment of congestive heart failure, and for use as probes to study the structure-function relationships of calcium channels.

Synthesis and calcium channel antagonist activity of nifedipine analogues containing 1,2-dihydropyridyl in place of the 1,4-dihydropyridyl moiety.

Calcium channel antagonist activities of the 1,2-dihydropyridines (9) were determined using the muscarinic-receptor mediated Ca2+ dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative potency order for 4-substituted analogs 9 was phenyl greater than 3-trifluoromethyl(nitro)phenyl greater than 4- and 2-trifluoromethyl(nitro)phenyl. Increasing the size of the alkyl ester substituents (9h) enhanced activity. The test results indicate that the 1,2-dihydropyridyl ring system (9) is partially bioisosteric with the 1,4-dihydropyridyl ring system (10). Competitive [3H]-nitrendipine binding studies indicated that the affinities of the 1,2-dihydropyridine analogues were much lower than expected from their ID50 activities, suggesting that these analogues inhibit calcium channels by a different receptor mechanism. In the synthetic work, Hantzsch condensation of aldehydes (3) with alkyl acetoacetates (4) afforded 3,5-dialkyl 2,6-dimethyl-4-(substituted-phenyl)-1,4-dihydropyridine-3,5-dicarboxylat es (5). Oxidation of 5 gave the aromatic pyridines (6) which were elaborated to the l-methylpyridinium methyl sulphates (7) and then to the perchlorates (8). Sodium borohydride reduction of 8 in aqueous ethanol gave 3,5-dialkyl 1,2,6-trimethyl-4-(substituted-phenyl)-1,2-dihydropyridine-3, 5-dicarboxylates (9).