Stereoselectivity of a potent calcium antagonist, 1-benzyl-3-pyrrolidinyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

Abstract

Four enantiomers (3a-d) of the title compound, YM-09730 (3), were synthesized by the reaction of (-)- or (+)-5-(methoxycarbonyl)-2, 6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (1a or 1b) with (S)- or (R)-1-benzyl-3-pyrrolidinol (2a or 2b). [3H]Nitrendipine binding affinity and coronary vasodilating activity of these compounds were evaluated. The absolute configuration of the most potent enantiomer (3a) with the longest duration was unequivocally determined to be (S)-1,4-dihydropyridine-C4 and (S)-pyrrolidine-C3 (S,S) by X-ray crystallographic study on 3a X HBr as well as 3a X HCl. The configuration of 1a corresponds to R, and the other enantiomers of 3 were respectively determined by chemical correlation. The potency order of the four enantiomers was (S,S)-3a greater than (S,R)-3b greater than (R,R)-3d greater than (R,S)-3c. Latent chiral characters of nifedipine derivatives with the identical ester groups were assigned by comparison of their puckering modes of 1,4-dihydropyridine (DHP) rings with those found in 3a X HCl or 3a X HBr. On the basis of the assignment, it has been revealed that the (S)-DHP nifedipine derivatives possess the synperiplanar carbonyl group at C5. The conformational restriction may be a factor causing stereoselectivity of antagonism.

Structure of methyl 2-(nitrooxy)ethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate

“…The large ring distortion is seen at C4 and N1. This is in agreement with other dihydropyridine derivatives reported previously (Tamazawa et al, 1986). …”

Structure of a 4-phenyl-1,4-dihydropyridine derivative containing a nitrooxyalkyl ester at the 3-position

“…A large ring distortion is seen at C4 and N1. This feature is observed in other dihydropyridine derivatives (Fossheim et al, 1982;Tamazawa et al, 1986). Lorentz and polarization corrections were applied to the data.…”

Reconsideration of vascular selectivity of dihydropyridine calcium antagonists: Comparison of cardiovascular profile of mepirodipine, a novel dihydropyridine consisting of a single stereoisomer with (+)-(S)-(S) conformation, with those of nifedipine and nicardipine.

“…Discussion Mepirodipine is a derivative of nicardipine and a single stereoisomer with (+)-(S)-(S) conformation (Fig. 1), whose K, value for in hibition of [3H]nitrendipine binding to rat brain cortex homogenate membranes was very markedly smaller, 0.205 nM, than those of the other three enantiomers (3.09 nM for (+)-(S)-(R), 49.6 nM for (-)-(R)-(S) and 14.3 nM for (-)-(R)-(R)) (11). The order of K,I values of the four enantiomers well-cor related to the potency order of their coronary vasodilator effects (11).…”

“…1), whose K, value for in hibition of [3H]nitrendipine binding to rat brain cortex homogenate membranes was very markedly smaller, 0.205 nM, than those of the other three enantiomers (3.09 nM for (+)-(S)-(R), 49.6 nM for (-)-(R)-(S) and 14.3 nM for (-)-(R)-(R)) (11). The order of K,I values of the four enantiomers well-cor related to the potency order of their coronary vasodilator effects (11). In the same study, the K, value of nifedipine was 4.65 nM and those of (+)-(S) and (-)-(R) nicardipine were 0.5 n M and 7.11 n M, respectively.…”

“…1), has been developed (11). It showed a potent long-lasting coronary vasodilator ef fect compared with the other three enan tiomers.…”