Synthesis and smooth muscle calcium channel antagonist effects of alkyl 1,4-dihydro-2,6-dimethyl-4-(pyridinyl)-5-[2-(4,5-dihydro-4,4-dimethylo xazolin-2-yl)]-3-pyridinecarboxylates

Article abstract of DOI:10.1002/ardp.19963290807

A group of racemic alkyl 1,4-dihydro-2,6-dimethyl-4-(3- or 4-pyridinyl)-5-[2-(4,5-dihydro-4,4-dimethyloxazolin-2-yl)]-3-pyridinec arboxylates 11a-e were prepared by using the Hantzsch reaction involving condensation of the Knoevenagel adducts 9a-e with 1-[2-(4,5-dihydro-4,4-dimethyloxazolin-2-yl)]-1-propen-2-amine (10). In contrast, the 4-(2-pyridinyl) analogue 11f was prepared by thionyl chloride mediated cyclization of the 5-{N-(1,1-dimethyl-2-hydroxyethyl)aminocarbonyl} moiety of 16 to the 5-[2-(4,5-dihydro-4,4-dimethyloxazolin-2-yl)] ring system (11f). In vitro calcium channel antagonist activity was determined by using the guinea pig ileum longitudinal smooth muscle (GPILSM) assay. Compared to the reference drug nifedipine (IC₅₀=1.43 x 10^-8 M), the title compounds 11 exhibited weak calcium channel antagonist activity (10^-5 to 10^-6 M range). A comparison of compounds 11 having a C-4 3-pyridinyl substituent showed that with respect to the alkyl ester R²-substituent, the relative potency order was i-Bu (11c)≤i-Pr (11e)>Me (11a). The point of attachment of the C-4 pyridinyl substituent in the isopropyl ester isomeric series of compounds was a determinant of activity where the potency profile was 4-py (11d)≤3-py (11e)>2-py (11f). Although less effective, the 4,5-dihydro-4,4-dimethyloxazolin-2-yl moiety acts as a bioisostere of the alkyl ester substituent present in classical 1,4-dihydropyridine calcium channel antagonists. The 4,5-dihydro-4,4-dimethyl-oxazolin-2-yl ring system is not an effective bioisostere of the 3-nitro group present in 1,4-dihydropyridine calcium channel agonists since isopropyl 1,4-dihydro-2,6-dimethyl-4-(2-pyridinyl)-5-[2-(4,5-dihydro-4,4-dimethy loxazolin-2-yl)]-3-pyridinecarboxylate (11f) produced a modest 10% increase in the in vitro contractile force of guinea pig left atrium at a concentration of 1.64 x 10^-7 M, relative to the reference 3-nitro analogue 1 (EC₅₀=9.6 x 10^-6 M).