High calcium antagonists

Isradipine (Fig. 7.5) is a further nifedipine analogue, which has been used in the treatment of hypertension either alone or in combination with diuretics. Isradipine possesses high calcium antagonist activity, which results in a peripheral vasodilatation without any detrimental effect on cardiac conduction. Its oral bioavailability is 90-95% of the administered dose, but the hepatic first-pass effect reduces this to 15-24%. Isradipine was shown to possess anti-atherosclerotic activity in a number of experimental models, but clinical studies (MIDAS) failed to confirm these findings in patients. 

Dihydropyridines not only are intermediates for the synthesis of pyridines, but also are themselves an important class of N-heterocycles an example is the coenzyme NADH. Studies on the function of NADH led to increased interest in the synthesis of dihydropyridines as model compounds. Aryl-substituted dihy-dropyridines have been shown to be physiologically active as calcium antagonists. Some derivatives have found application in the therapy of high blood pressure and angina pectoris. For that reason the synthesis of 1,4-dihydropyridines has been the subject of intensive research and industrial use. The Hantzsch synthesis has thus become an important reaction. 

H. Fujimoto, I. Nishino, K. Ueno and T. Umeda, Determination of the enantiomers of a new 1,4-dihydropyridine calcium antagonist in dog plasma achiral / chiral coupled high performance liquid cliromatography with electrochemical detection , 7. Pharm. Sci. 82 319-322(1993). 

Application of part of the classical Hantzsch pyridine synthesis leads to nifedipine (87) (81 AG(E)762, 68SAP6801482), a calcium antagonist useful in the treatment of angina. The pharmacology of a chemically related drug, nisoldipine (88), has recently been studied (80AF2144). Both compounds inhibit the transmembrane movement of calcium into activated smooth and cardiac muscle. Nisoldipine, however, is characterized by a high potency and uniqueness of action and may well prove to be of considerable therapeutic value. 

Quinidine [KWIN i deen] is the prototype Class IA drug. At high doses, it can actually precipitate arrhythmias, which can lead to fatal ventricular fibrillation. Because of quinidine s toxic potential, calcium antagonists, such as verapamil, are increasingly replacing this drug in clinical use. 

However, as already mentioned earlier, high pressure liquid chromatography with tandem mass spectrometric detection (LC-MS/MS) has evolved in the last few years as the major bioanalytical technique for the bioanalysis of analytes in biological matrices. This is reflected also in a number of LC-MS/MS assays for the determination of dihydropyridine calcium antagonists in biological fluids (Carvalho et al. 2001, Schug et al. 2002 Kang et al. 2004). 

Bossert VE, Meyer H, WehingerE (1981)4-Aryldihydropyridine, anew class of highly active calcium antagonists. Angew Chem 93 755-763... 

Treatment still remains difficult, because few clinical studies are available. High doses of calcium antagonists are recommended, but their frequent side effects have to be taken into account, particularly with a cardiac output of <2 1/min. (146) In severe cases, pulmonary pressure reduction by permanent infusion of epoprostenol over several weeks or long-term administration of oxygen may be helpful. Good experience has been made with the endothelin-receptor antagonist bosentan (2 x 125 mg/day). (36) (s. p. 338 )... 

Bossert, F., Meyer, H., Wehinger, E. 4-Aryldihydropyridine, a new class of highly active calcium antagonists. Angew. Chem. 1981, 93, 755-763. 

W. W. Holt, M. F. Wendland, N. Derugin, C. Wolfe, M. Saeed, C. B. Higgins, Effects of nicardipine, a calcium antagonist, on myocardial salvage and high energy phosphate stores in reperfused myocardial injury, J Am Coll Cardiol 16, 1736-1744 (1990). 

The types of enzymes used by organic chemists vary widely and include such well-known biocataiysts as lipases, esterases, oxidoreductases, oxinitrilases, transferases and aldolases [4]. An example which illustrates the industrial application of a lipase concerns the kinetic resolution of a chiral epoxy ester used as the key intermediate in the synthesis of the calcium antagonist Diltiazem, a major therapeutic in the treatment of high blood pressure [6] (Fig. 1). In developing the industrial process for the production of this drug, many different lipases were screened, but only the bacterial lipase from Serratia marescens showed both a sufficiently high activity and enantioselectivity. The intermediate is produced industrially on a scale of 50 tons/year. 

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