| Autor: |
Ramesh, M., Matowe, W. C., Akula, M. R., Vo, D., Dagnino, L., Li-Kwong-Ken, M. C., Wolowyk, M. W., Knaus, E. E. |
| Zdroj: |
Journal of Medicinal Chemistry; February 12, 1998, Vol. 41 Issue: 4 p509-514, 6p |
| Abstrakt: |
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 × 10-6 M) than the (−)-enantiomer (IC50 = 7.48 × 10-8 M) on GPILSM. In the GPLA assay, (+)-14a exhibited a much more potent agonist effect (EC50 = 8.45 × 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. |
| Databáze: |
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