Synthesis and Calcium Channel Antagonist Activity of Dialkyl 4-(Dihydropyridinyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinecarboxylates

Article abstract of DOI:10.1021/jm00387a010

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- 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 deg 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) > 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.