Nifedipine, structure

The probably most striking example so far of solvent influence on enzyme selectivity has been found by Yoshihiko Hirose and co-workers at the Amano Corp. in Nagoya, Japan, studying nifedipines, which provide a befitting conclusion of this chapter and a transition to the next on use of enzyme catalysis in the pharma industry. Nifedipines, structurally 1-substituted dihydropyridine mono- or diesters, are used in cardiovascular therapy, where they are termed calcium antagonists (Goldmann, 1991) the most prominent representative is Adalat from Bayer (Leverkusen, Germany). While the simplest achiral dihydropyridines can be syn-... 

FIGURE 17.25 The structures of nifedipine and ryanodine. Nifedipine binds with high affinity to the Ca" -release channels of t-tubules. Ryanodine binds with high affinity to the Ca" channels of SR terminal cisternae. 

This section deals with the application of molecular orbital (MO) calculations in structure-activity relationship (SAR) analyses. Calcium channel-blocking 1,4-dihydropyridine (DHP) derivatives such as nifedipine (Fig. 9.10) are widely used in the therapy of cardiovascular disorders. 

FIGURE 4.20 Structures of the CYP3A4 substrates, erythromycin, nifedipine, testosterone, and midazolam, and their metabolites. 

Fig. 4.8 Structures of the dihydropyridine calcium channel blockers, nifedipine (neutral) and amlodipine (basic).

Bepridil also inhibits fast sodium inward channels. Galcium channel blockers are classified by structure as follows Diphenylalkylamines - verapamil benzothiazepines - diltiazem dihydropyridines - amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine. 

Differential thermal analysis (heating cycles of 90-200°C) of the pure nifedipine, empty Eudragit microspheres and microspheres containing various amounts of nifedipine was carried out to evaluate the internal structure alter drug incorporation. 

It can therefore be deduced that nifedipine at this concentration in the Eudragit microspheres was present in either a molecular dispersion or a solid solution state. This was also confirmed by the SEM analysis. It can be seen from Figs 1 and 3 that microspheres containing up to 5% nifedipine had very smooth surfaces. There was no evidence of macroscopic pores. Formation of fine nifedipine crystals seemed to have no effect on the surface structure of the nifedipine microspheres when the drug payload was 4.8% (w/w). However, three microspheres did not appear totally spherical. 

Calcium channel blockers (CCBs) prevent the flow of calcium ions through channels in heart tissue. Inhibiting calcium flow decreases the strength of contraction of the heart and decreases blood pressure. Most CCBs fall into the dihydropyridine structural class, with nifedipine (Adalat, A.132) being the prototypical example (Figure A.38). Nondihydropyridine CCBs include diltiazem (Cardizem, A.135) and verapamil (Calan, A.136). 

A2. Amann, K., Nichols, C., Tornig, J., Schwarz, U., Zeier, M., Mall, G., and Ritz, E., Effect of ramipril, nifedipine, and moxonidine on glomerular morphology and podocyte structure in experimental chronic renal failure. Nephrol. Dial. Transplant. 11, 1003—1011 (1996). 

The reaction of ethyl acetoacetate, benzaldehyde, and urea leads to ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-phenyl-5-pyrimidinecarboxylate. This reaction (the so called Biginelli reaction) was discovered over 100 years ago [93T6937], Interest in these dihydropyrimidines has increased rapidly mainly due to their close structural relationship to the pharmacologically important dihydropyridine calcium channel blockers of the nifedipine-type [93T6937], The dibromo (51) and monobromo derivatives (55) of the most simple Biginelli compounds mentioned above are readily obtained by bromination [93T6937], and the reactions of these derivatives with sodium azide have been studied recently [90LA505] [91 JCS(P1)1342],... 

A4 Midazolam, Testosterone (strongly recommended to use at least two structurally unrelated substrates) Nifedipine, Felodipine, Cyclosporine, Terfenadine, Erythromycin, Simvastatin Ketoconazole (recent evidence that it is also a potent inhibitor of 2C8), Troleandomycin Cyclosporine... 

Analogous to the majority of dihydropyridines, nifedipine s, nitrendipine s, and nimodipine s chemical structures - a 2- or 3-nitrophenyl substituent in the 4-position combined with the dihydropyridine diester structure - results in a high response in electron capture detection (ECD), thus allowing high detection sensitivity and sufficient assay specificity towards endogenous compounds, metabolites or common co-medications (Muck et al. 1994). 

Hypersensitivity to nifedipine and structurally related calcium channel antagonists... 

Figure 4.11 Structure of a nifedipine-inspired SP 1,4-dihydropyridine library LIO.

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