Atenolol enantiomers

He, J., Shibukawa, A., Nakagawa, T., Wada, H., Fujima, H., Imai, E., Go-oh, Y. (1993). Direct injection analysis of atenolol enantiomers in plasma using an achiral/chiral coupled column HPLC system. Chem. Pharm. Bull. 41, 544—548. 

Mehvar, R., Gross, M.F. Kreamer, R.N. (1990) Pharmacokinetics of atenolol enantiomers in humans and rats. Journal of Pharmaceutical Sciences, 79, 881-885. 

Rosseel, M.T. Vermeulen, A.M. Belpaire, F.M. Reversed-phase high-performance liquid chromatographic analysis of atenolol enantiomers in plasma after chiral derivatization with (-l-)-l-(9-flu-orenyl)ethyl chloroformate. J.Chromatogr., 1991, 568, 239—245... 

Mehvar, R. Liquid chromatographic analysis of atenolol enantiomers in human plasma and urine. 

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

Although very efficient, the broad application of the direct preparation is restricted due to the limited number of pure starting enantiomers. The design of a multistep process that includes asymmetric synthesis is cumbersome and the development costs may be quite high. This approach is likely best suited for the multi-ton scale production of commodity enantiomers such as the drugs ibuprofen, naproxen, atenolol, and albuterol. However, even the best asymmetric syntheses do not lead to products in an enantiomerically pure state (100 % enantiomeric excess). Typically, the product is enriched to a certain degree with one enantiomer. Therefore, an additional purification step may be needed to achieve the required enantiopurity. 

Wren et al. (24) determined the binding constants of the enantiomers of propranolol and atenolol with DM-/3-CD. The results explained well the experimental observations on the separation of the enantiomers of these compounds in CE. In particular, the enantiomers of propranolol, for which the binding constants and the binding selectivities (KR/KS) were higher, were resolved better and at lower DM-/3-CD concentration than were the enantiomers of atenolol. 

Pure enantiomer imprinting of L-phenylalanine anilide, (/ )-propranolol, S)-metoprolol and (50-ropivacaine has been undertaken and these MIP capillaries have been used in the CEC mode for enantiomer separations [39-41,60-62,70,71] (Table 16.1). Baseline separations for the enantiomers of phenylalanine (Fig. 16.7) and for propranolol and metoprolol could be carried out in less than 2 min. (Fig. 16.5). A propranolol column was shown to be able to resolve several other j8-blockers, including prenalterol, atenolol, pindolol, etc. (Fig. 16.8) [41] and the ropi-... 

Fig. 16.8. Enantiomer separations of (A) rac-prenalterol, (B) rac-atenolol and (C) rac-pin-dolol on a capillary column containing imprints of (7 )-propranolol. This demonstrates the ability of a MIP to recognise structural analogues of the template molecule used for the imprint preparation. Reprinted from [41] Copyright (1997), with permission from Wiley-VCH.

It is expected that similar to method reported previously based on the use of cyclodextrins and sucrose the present method should have high sensitivity. Its sensitivity can be evaluated from two values the lowest enantiomeric excess (EE% which is defined as EE% = [(R-enantiomer - S-enantiomer)/(R-enantiomer + S-enantiomer)]) that can be determined at the lowest concentration of a sample. It should be noted that these two terms are interdependent to each other, namely, the limit of detection (LOD) on ee% can be improved by increasing sample concentration or vice versa. In an attempt to estimate the sensitivity of the method, we performed measurements on 10 samples of 10.0 mM or 2.66 mg/mL of atenolol with different cc% s in S- CHTA Tf2N. Results obtained are listed in Table 2. It is evident from the table that the method is not only effective but also very sensitive. It can accurately determine samples with concentration as low as micrograms having ee value as high as -90.00% (or +97.00% ) and as low as 0.6%. Furthermore, even at ee as low as 0.6%, the relative error was only 3.33%. 

Figure 3. Predicted enantiomeric composition versus actual composition for 60 mM of (A) ibuprofen (B) atenolol (C) phenylalanine and (D) alanine in S-CI ITA TI tN ionic liquid. Filled circles, S-enantiomers for ibuprofen and propranolol and L-enantiomers for phenylalanine and alanine Open circles, R-enantiomers for propranolol and D-enantiomers for phenylalanine and alanine.

These results have led to an interesting industrial apphcation for the synthesis of the j5-blockers Metoprolol and Atenolol. Thus, epoxidation of the prochiral allyl ethers by several bacteria, including the P. oleovorans strain mentioned above, led to the corresponding (S)-epoxides which showed excellent enantiomeric purities (Fig. 3). Further on, these chirons (i.e. chiral building blocks) were transformed into the corresponding (S)-enantiomers of the drugs developed by the Shell and Gist-Brocades companies [44]. Refinement of this approach... 

Stoschitzky, K. Kahr, S. Donnerer, J. Schumacher, M. Luha, O. Maier, R. Klein, W. Lindner, W. Stereoselective increase of plasma concentrations of the enantiomers of propranolol and atenolol during exercise. Clin.Pharmacol.Ther., 1995, 57, 543-551... 

Miller, R.B. Guertin, Y. High-performance liquid chromatographic assay for the derivatized enantiomers of atenolol in whole blood. J.Liq.Chromatogr., 1992, 15, 1289-1302... 

Sallustio, B.C. Morris, R.G. Horowitz, J.D. High-performance liquid chromatographic determination of sotalol in plasma. I. Application to the disposition of sotalol enantiomers in humans. J.Chromatogr., 1992, 576, 321-327 [atenolol is IS extracted sotalol derivatization chiral achiral fluorescence detection UV detection plasma SPE]... 

Chin, S.K. Hui, A.C. Giacomini, KM. High-performance liquid chromatographic determination of the enantiomers of beta-adrenoceptor blocking agents in biological fluids. II. Studies with atenolol. J.Chromatogr., 1989, 489, 438—445... 

Wilson, M.J. Ballard, K.D. Walle, T. Preparative resolution of the enantiomers of the beta-blocking drug atenolol by chiral derivatization and high performance liquid chromatography. J.Chromatogr, 1988, 431, 222-227... 

Figure 3 Powder x-ray diffraction patterns of (a) the racemic compound (upper trace) and an enantiomer (lower traces) of norephedrine hydrochloride, and (b) the pseudoracemate (-1-/—) and an enantiomer (—) of atenolol. Shift of peak position is indicated by an asterisk and is characteristic of a solid solution. (From Ref. 17. Reproduced by permission of the American Pharmaceutical Association.)...

It has been demonstrated that both hydrophilic (e.g., atenolol) and lipophilic (e.g., propranolol) beta-blockers are stored in and released from the adrenergic nerve endings [29]. Furthermore, it has been reported [29,30] that the uptake and release of atenolol from the models of adrenergic cells are stereoselective, favoring the more active (—) enantiomer of atenolol by 200 to 500%. Additionally, a study in humans [31] chronically receiving... 

The two enantiomers of a racemic drug may interact with each other at different pharmacokinetic or pharmacodynamic levels. This type of interaction has been studied for atenolol [2] and propranolol [51 53]. For atenolol, there was no pharmacokinetic or pharmacodynamic interaction between the two enantiomers the half-dosed S(—)-atenolol produced the same effect as did the racemic atenolol [2]. Additionally, the plasma concentration-time profiles of S(—)-atenolol were identical after the administration of the racemate and the half-dosed pure enantiomer. On the other hand, both single [51] and multiple [52] dose studies have shown that there is a significant interaction between the enantiomers of propranolol. When administered as pure enantiomer, as opposed to the racemate, R(- -)-propranolol tends to show lower plasma concentrations [52]. However, the kinetics of the more active S(—)-enantiomer appear to be the same whether it is administered as a pure enantiomer or racemate [51-53]. 

The three protein stationary phases behave very similarly, in that retention and chiral selectivity is controlled by pH and the concentration of solvent in the mobile phase. However, the selectivity for a given enantiomer pair can be very different on each stationary phase despite the fact that they are all protein based. This is demonstrated in figure 8.3. The retention of the enantiomers of Talinolol and Atenolol decrease with increase in 2-propanol in the mobile phase which, if largely retained by dispersive interactions, would be expected. However, the chiral selectivity oi the stationary phase to the two pairs of enantiomers of the stationary phase to the two pairs of enantiomers increases with the 2-propanol content of the mobile phase. This would indicate that the chiral selectivity was more likely to be due to polar interactions. However, it is interesting to note that although the retention of Kynurenine also falls with increase 2-propanol concentration, when separated on the CHIRAL-HSA phase, the chiral selectivity also /fa. 

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