Diltiazem structure

L-type calcium channels (voltage-gated calcium channels L-subtype) Similarity to Diltiazem and a second ligand. ZINC db ( 50 K commercially available subset screened but most filtered to achieve desired PK profile using VolSurf). SHOP similarity, and feature-presence filtering down to 36 compounds 7 hits 18 tested, active in a vasorelaxant assay and some had novel structures. [67]... 

Fig. 7.13 Structures of diltiazem and a benzozapepinone analogue resistant to metabolism.

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. 

Important differences in vascular selectivity exist among the calcium channel blockers. In general, the dihydropyridines have a greater ratio of vascular smooth muscle effects relative to cardiac effects than do diltiazem and verapamil. Furthermore, the dihydropyridines may differ in their potency in different vascular beds. For example, nimodipine is claimed to be particularly selective for cerebral blood vessels. Splice variants in the structure of the cq channel subunit appear to account for these differences. 

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). 

The dihydropyridine class of calcium channel blockers undergoes extensive first-pass oxidation by CYP3A isoforms to their pyridine metabolites, and several studies have shown that inducers and inhibitors of these P450s decrease and increase the blood concentrations of the active dihydropyridine structures, respectively (51). The calcium channel blockers verapamil and diltiazem are unrelated structures that also undergo significant metabolism by cytochromes... 

The thermodynamic and structural effects of diltiazem on lecithin (PC) liposomes have been studied by DSC and X-ray diffraction [154]. The authors found that at higher drug concentration the pretransition disappears, the main transition temperature decreases, and the lamellar thickness of the bilayer increases. The chains in the (3-conformation were packed in a hexagonal undistorted lattice. There was a complete agreement in the observed data all changes in the calorimetric and structural curves (X-ray) occurred at the same concentration, that is between 1(T2 and KT1 M. 

Four categories of calcium channel blockers can be defined based on their chemical structures and actions diphenylalkylamines, benzothiazepines, dihydropyridines, and bepridil. Both diphenylalkylamines (verapamil) and benzothiazepines (diltiazem) exhibit effects on both cardiac and vascular tissue. With specificity for the heart tissue, these two types of calcium channel blockers can slow conduction through the AV node and are useful in treating arrhythmias. The dihydropyridines (nifedipine is the prototypical agent) are more potent peripheral and coronary artery vasodilators. They do not affect cardiac conduction, but can dilate coronary arteries. They are particularly useful as antianginal agents. Bepridil is unique in that it blocks both fast sodium channels and calcium channels in the heart. All calcium channel blockers, except nimodipine and bepridil, are effective in treating HTN. 

The spectrum obtained is consistent with the structure of diltiazem hydrochloride. 

There are approximately a dozen calcium channel antagonists marketed in the United States for the treatment of hypertension, certain dysrhythmias, and some forms of angina (see Chaps. 13,15, and 17). The calcium channel blockers are classified by their chemical structure as phenylalkylamines (e.g., verapamil), benzothiapines (e.g., diltiazem), and dihydropyridines (e.g., amlodipine, felodipine, nicardipine, and nifedipine). Several of these agents, namely, diltiazem, nicardipine, nifedipine, and verapamil, are formulated as sustained-release oral dosage forms or have a slow onset of action and longer half-life (e.g., amlodipine " ), allowing once-daily administration. 

Theoretically it should be possible to classify the slow channel blockers according to whether or not they affect the kinetics of slow channel transport. In this way we could readily separate the nifedipine type of drugs from those that are more like verapamil. Alternatively can these drugs be subgrouped according to their chemistry This possibility seems to be remote. Thus diltiazem is a benzothiazepine derivative (Figure 1 nifedipine is derived from dihydropyridine whilst verapamil has some structural features in common with papaverine. 

Structure activity relationships are available for verapamil and nifedipine but not, as yet, for diltiazem. 

KB944 (4) is a recently developed calcium channel blocking drug. It has a similar pharmacological profile to diltiazem [86]. Few structure-activity data are available, but it has been reported that the introduction of a pyridine nitrogen into the phenyl ring and variations in the alkoxy substitution at the phosphorus atom are possible without loss of activity [75]. 

However, the potency of a series of 1,4-dihydropyridines to inhibit [3H]ni-trendipine or [3H]nimodipine binding correlates well with the rank order of these compounds for inhibition of cardiac inotropic responses and for inhibition of smooth muscle contraction [26, 70, 85, 90, 104, 127]. This implies that the structure-activity dependence is similar for both binding and pharmacological activities, even if there is a difference in the concentrations at which effects are found [70]. Furthermore, diltiazem not only stimulates the binding of [3H]nimodipine to canine cardiac sarcolemma but also potentiates the negative inotropic response of perfused rat hearts to nimodipine [ 146]. Thus,... 

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