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

• Published in: Journal of medicinal chemistry 1995-07, Vol.38 (15), p.2830-2841
• Main Authors: Alajarin, Ramon, Vaquero, Juan J, Alvarez-Builla, Julio, Pastor, Manuel, Sunkel, Carlos, Fau de Casa-Juana, Miguel, Priego, Jaime, Statkow, Peter R, Sanz-Aparicio, Julia, Fonseca, Isabel
• Format: Article
• Language: English
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - pharmacology; Cardiovascular system; Chemical Phenomena; Chemistry, Physical; Condensed matter: structure, mechanical and thermal properties; Crystallography, X-Ray; Dihydropyridines - chemical synthesis; Dihydropyridines - chemistry; Dihydropyridines - pharmacology; Drug Evaluation, Preclinical; Exact sciences and technology; Guinea Pigs; Heart - drug effects; Heterocyclic compounds; In Vitro Techniques; Isradipine - metabolism; Kinetics; Medical sciences; Miscellaneous; Molecular Conformation; Molecular Structure; Muscle Contraction - drug effects; Muscle, Smooth, Vascular - drug effects; Myocardial Contraction - drug effects; Myocardium - metabolism; Organic compounds; Pharmacology. Drug treatments; Physics; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure of solids and liquids; crystallography; Structure of specific crystalline solids; Structure-Activity Relationship; Tritium
• ISSN: 0022-2623; 1520-4804
• 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 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.