Nifedipine analogs

With 19 additional nifedipine analogs, a second model was constructed supporting the above-mentioned receptor hypothesis of the resting state model (r.m.s.d. = 0.409 kcal mol-1 for the test set derivatives). 

Fig. 6.10 Formula of the hypothetical nifedipine analog used in the MD simulation of Alper and Stouch [60].

Another difference between the two simulations was related to conformational transitions from trans to cis orientation of the ester groups of the nifedipine analog. 

Kumar PP, Stotz SC, Paramashivappa R et al. (2002) Synthesis an evaluation of a new class of nifedipine analogs with T-type calcium channel blocking activity. Mol Pharmacol 61(3) 649-658... 

Hemmateenejad B, Akhond M, Miri R, Shamsipur M. Genetic algorithm applied to the selection of factors in principal component-artificial neural networks application to QSAR study of calcium channel antagonist activity of 1,4-dihydropyri-dines (nifedipine analogs). J Chem Inf Comput Sci 2003 43 1328-34. 

Gaudio AC, Korolkovas A, Takahata Y. Quantitative structure-activity relationships for 1,4-dihydropyridine calcium channel antagonists (nifedipine analogs) a quantum/ classical approach. J Pharm Sci 1994 83 1110-1115. 

Meyer and co-workers were one of the first groups to use preformed enamines to synthesize 1,4-dihydropyridines in their synthesis of unsymmetrical fiased nifedipine analogs. Michael addition of alkylidene acetoacetic esters substituted with various aryl groups 188 and enaminocarbonyls 189 (where = 1 or 2) in the presence of refluxing ethanol led to the corresponding fused systems 190 in good yield. 

Dihydropyridines (DHPs), such as nifedipine, were introduced to clinical medicine in 1975 to treat cardiovascular diseases, such as hypertension, cardiac arrhythmias or angina [70]. Many nifedipine analogs were synthesized and the dihydropyridiminone 11 (Figure 12) was demonstrated as the first DHP derivative to exhibit moderate hypotensive and coronary relaxation properties [71]. 

Nicardipine Nicardipine, l,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-methyl-2-[(methyl-phenylmethyl)-amino]ethyl ester 3,5-pirididincarboxylic acid (19.3.7), is synthesized in a manner analogous to the synthesis of nifedipine, the only difference being that in the Hantsch synthesis, two different )3-dicarbonyl compounds are used simultaneously with o-nitrobenzaldehyde. During this, one of these in the enamine form of acetoacetic ester is simultaneously used as an amine component. A heterocycUzation reaction is accomplished by reacting, the methyl ester of 8-aminocrotonic acid with the 2-methyl-2-benzyl-aminoethyl ester of acetoacetic acid [24-27]. 

The preparation of nifedipine and other simple symmetric analogs is very straightforward (Scheme 11.1). 4-Aryldihydropyridine-3,5-dicarboxylates are isolable intermediates... 

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). 

Plotkin CN, Eckenbrecnt PD, Waldo DA. Consecutive cardiac arrests on induction of anesthesia associated with nifedipine-induced carotid sinus hypersensitivity. Anesth Analog 1989 68(3) 402-5. 

Kappe, C. 0.4-Aryldihydropyrimidines via the Biginelli condensation aza analogs of nifedipine-type calcium channel modulators. 

Cayl channels (L-type) are targets of calcium-channel blockers or calcium antagonists which decrease the influx of Ca + in cardiac and smooth muscle vascular cells dihy-dropyridines (nifedipine and analogs), phenylalkylamines (verapamil) and benzothiazepines (diltiazem), widely used as antihypertensive, antianginal and antiarrhythmic drugs. Cayl openers, like Bay K 8644, have been synthesized but have not found any therapeutic interest. 

As yet there are few quantitative structure-activity studies for the Ca + channel antagonists. However, qualitative indices of structure-function dependence are available, particularly for the 1,4-dihydropryidines of the nifedipine class where, because of the comparative ease of synthesis (43), a large number of analogs are available. 

TABLE II Pharmacologic Activities of Ester-Substituted Analogs of Nifedipine (63,64)... 

The Ca +-channel antagonists, the 1,4-dihydropyridines (DHPs), represent a remarkably successful group of cardiovascular drugs that have antihypertensive, antiangi-nal, and antiarrhythmic properties (167). Nifedipine (Fig. 10.8) was the first member of the DHP family a structure that embraces both Ca -channel antagonists and activators (168), which was followed by the synthesis of a number of analogs with a prolonged duration cf action and enhanced vascular selectivity (167). 

Amlodipine 20 Calcium-channel (blocker) Analog of nifedipine Synthetic compound libraries derived from the Hantzch reaction Overcame short duration- Angina and hypertension Peripheral vasculature... 

Bossert and co-workers original three-component Hantzsch synthesis of nifedipine used 1 equiv of 2-ntirobenzaldehyde 181, 2 equiv of methyl acetoacetate 180, and ammonia to give nifedipine in 72% yield. Since their report, a number of variations on the Hantzsch 1,4-dihydropyridine synthesis have been reported. Many of the initial reports on the synthesis of 1,4-dihydropyridine derivatives were aimed at studying the structure activity relationships of these compounds with the goal of developing more potent and specific analogs of nifedipine. 

In a later report, Meyers used ethyl acetoacetate 8, aromatic aldehydes such as 3-nitrobenzaldehyde 192, and 2,2-methylenediimidazoline hydrochloride 196 to produce the corresponding 1,4-dihydropyridine 197 as a more complex derivative of nifedipine in 65% yield. A series of aromatic aldehydes were employed to generate additional 1,4-dihydropyridines of this nature in 14-74% yield (not shown). Meyers and co-workers also prepared several novel analogs by varying the ketone source to produce compounds such as 198, or by using the Michael addition products of various aldehydes and ketones to produce compounds such as 199. 

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