Synthesis, structure, and pharmacological evaluation of the stereoisomers of furnidipine.
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 diastereomeric mixtures thus obtained were separated by chromatography, using poly(D-phenylglycine) as the chiral stationary phase. The enantiomeric purity of the stereoisomers was determined by a high-performance liquid chromatography-chiral stationary phase technique (HPLC-CSP). Attempts to obtain crystals of a single stereoisomer failed in different solvents, 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 crystallography. 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.
Alajarin
R
R
Departamento de Química Orgánica, Universidad de Alcalá, Madrid, Spain.
Vaquero
J J
JJ
Alvarez-Builla
J
J
Pastor
M
M
Sunkel
C
C
Fau de Casa-Juana
M
M
Priego
J
J
Statkow
P R
PR
Sanz-Aparicio
J
J
Fonseca
I
I
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D017275:Isradipine / Q000378:metabolism; D007700:Kinetics; D008968:Molecular Conformation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014316:Tritium
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D014316:Tritium; C082391:furnidipine; D017275:Isradipine