Synthesis, Structure, and Pharmacological Evaluation of the Stereoisomers of Furnidipine

Article abstract of DOI:10.1021/jm00015a005

The synthesis and pharmacological activities of the four stereoisomers of methyl tetrahydrofuran-2-ylmethyl 2,6-dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (furnidipine) are reported.The four isomers were synthesized by a modified Hantzsch synthesis by reaction of (-)- or (+)-tetrahydrofuran-2-ylmethyl 3-aminocrotonate and methyl 2-<(2'-nitrophenyl)methylene>acetoacetate or, alternatively, by reaction of (-)- or (+)-tetrahydrofuran-2-ylmethyl 2-<(2'-nitrophenyl)methylene>acetoacetate and methyl 3-aminocrotonate.The 1:1 diasteromeric mixture thus obtained were separated by chromatography, using poly(D-phenylglycine) as the chiral stationary phase.The enantiomeric purity of the stereoisomers was determined by high-performance liquid chromatography-chiral stationary phase technique (HPLC-CSP).Attempts to obtain crystals of a single stereoisomer failed in different solvent, while methanol crystallization of the product obtained from (+/-)-tetrahydrofuran-2-ylmethyl 2-<(2'-nitrophenyl)methylene>acetoacetate and methyl 3-aminocrotonate yielded good-quality crystals of the most insoluble racemate which proved to be a mixture of the (SS)/(RR) enantiomers by X-ray crystaloography.Conformational analysis of the stereoisomers, assuming rotation of the aryl substituent and ester groups, shows small energy differences (about 4 kcal*mol^-1) between the most and the least favorable conformations.Binding studies were performed using <3H>isradipine as a reference ligand.The results showed stereospecificity of the furnidipine isomers in brain, ileum, and cardiac tissues, the (SS) and (SR)-isomers clearly being more potent than their (RR)- and (RS)-enantiomers.The (SS)- and (SR)-isomers were also more selective on cerebral tissue when compared with ileal and cardiac preparations.