Synthesis and smooth muscle calcium channel effects of dialkyl 1,4-dihydro-2,6-dimethyl-4-aryl-3,5-pyridinedicarboxylates containing a nitrone moiety in the 4-aryl substituent

A group of dialkyl 1,4-dihydro-2,6-dimethyl-4-{3- (or 4-)[[(Z)-N-oxo-N-[4-substituted-phenylmethylene (or vinylmethylene)]-lambda(5)-azanyl]phenyl}-3,5-pyridinedicarboxylates 7a-n were synthesized. Reaction of the C-4 nitrophenyl compounds 6-d with an aryl Grignard reagent afforded the corresponding nitrone derivatives 7a-e. Alternatively, reaction of the aryl hydroxylamine compounds 8a-b prepared by reduction of the nitrophenyl compounds 6c-d with Zn/NH4Cl, or the aryl hydroxylamine compounds 8c-d prepared by reduction of the nitrophenyl compounds 6e-f with 5% rhodium-on-charcoal and 65% hydrazine hydrate, with a 4-substituted-benzaldehyde, benzaldehyde or acrolein afforded the respective nitrone compounds 7f-n. In vitro calcium channel (CC) antagonist activities were determined using the guinea pig ileum longitudinal smooth muscle assay. This class of compounds containing a nitrone moiety on the 1,4-dihydropyridine C-4 phenyl ring exhibited CC antagonist activities (10(-5) to 10(-9) M range) to the reference drug nifedipine (IC50 = 1.43 x 10(-8) M). Structure-activity relationships showed that the position of the nitrone moiety on the C-4 phenyl ring was a determinant of CC antagonist activity where the potency order was always meta-nitrone > para-nitrone. The effect of the ester alkyl substituent was variable depending upon whether the nitrone substituent was at the meta or para-position (meta-nitrone, Et > i-Pr approximate to Me; para-nitrone, i-Pr > Me approximate to Et). In the diethyl ester series of compounds having a meta-nitrone moiety, the difference in potency for the various R-2-nitrone substituents varied by a factor of 15-fold (IC50 = 1.51 x 10(-7) to 9.84 x 10(-9) M range) (4-Cl-C6H4- greater than or equal to 4-Me-C6H4- approximate to C6H5- greater than or equal to 4-O2N-C6H4- 4-F3C-C6H4- much greater than CH2=CH-). Whole-cell voltage-clamp studies using isolated guinea pig ventricular myocytes indicated that the 4-{3-[(Z)-N-oxo-N-(phenylmethylene)-lambda(5)-azanyl]phenyl} compound 7c (10 mu M) is a calcium channel antagonist which decreased the calcium current (I-Ca).