Stereoselectivity of a potent calcium antagonist, 1-benzyl-3-pyrrolidinyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.
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.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000138:chemical synthesis*; D015220:Calcium Channels; D002540:Cerebral Cortex / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008968:Molecular Conformation; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D009568:Nitrendipine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D011978:Receptors, Nicotinic; C050699:mepirodipine; D009568:Nitrendipine; D009543:Nifedipine