Distomer

Although it might seem that adrninistration of enantiomericaHy pure substances would always be preferred, the diuretic indacrinone (3), is an example of a dmg for which one enantiomer mediates the harmful effects of the other enantiomer (4). (+)-Indacrinone, the diureticaHy active enantiomer or eutomer causes uric acid retention. Fortunately, the other enantiomer distomer) causes uric acid elimination. Thus, adrninistration of a mixture of the two enantiomers, although not necessarily racemic, may have therapeutic value. 

Analog ent-(+)-8 is 20-fold more potent than racemic acifran and is threefold more potent than niacin in the cAMP whole-cell assay [55]. The selectivity was also improved with respect to acifran with 10-fold selectivity for GPR109A over GPR109B. The importance of the absolute configuration of ent-(+)-8, which is tentatively assigned S, is demonstrated by the 70-fold better cAMP whole-cell activity of the eutomer compared to that of the distomer. 

HP-jS-CD were added. All compounds were resolved in 20 min (see Figure 5). The data indicated that the validated method offered equivalent and complementary information, in terms of selectivity, sensitivity, accuracy, linearity, and precision, to that of an established gradient LC method employed for similar purposes. Ragaglitazar is a dual peroxisome proliferator-activated receptor ot and y agonist intended to restore insulin sensitivity and correct diabetic dyslipidemia. A chiral CZE method combining two CDs, sulfobutylether-jS-CD and dimethyl-/i-CD, lent itself to the analysis of ragaglitazar, its distomer (the (+)... 

Figure 3.7 Determination of the enantiomeric purity of SB-214857 API using CD-modified CE. Distomer content measured at 0.06% by area. (Conditions plain fused silica capillary, 50 cm effective length, 57 cm total length, 75 pm i.d. buffer lithium phosphate [pH 3.0, 100 mM] containing 0.05% (w/v) hydroxyethy[cellulose and 1.5 mM dimethyl- 8-CD voltage 30 kV temperature 20°C detection UV at 200 nm sample preparation 0.2 mg/ml in water sample introduction 5 s at 35 mbar, capillary inlet at anode.)...

Figure 3.10 Determination of the enantiomeric purity of propranolol API using packed-column chiral SFC. Distomer content measured at 0.04% by area. (Conditions CHIRALCEL OD 25 cm X 0.46 cm i.d. mobile phase carbon dioxide methanol containing 0.5% isopropylamine [70 30, v/v isocratic] flow rate 4 ml/min constant outlet back-pressure regulator 200 bar detection UV at 220 nm column temperature 30 C injection volume 10 fil.)...

It is common to call the most active enantiomer eutomer and the less active one distomer. The ratio of the pharmacological activity of these are called the eudismic ratio (ER) and Pfeiffer s mle states that the lower the effective dose of a drug the greater the difference in the pharmacological effect of the optical isomers . When two enantiometic... 

Lehman et al. (1986) stated the definitions of stereoselectivity in the following manner the better fitting enantiomer (the one with higher affinity for the receptor) is called the eutomer, whereas the one with the lower affinity is called the distomer. The ratio of... 

In a series of agonists and antagonists (for definitions, see section 2.4), the eudismic affinity quotient can also he defined as a measure of stereoselectivity. Because of widespread misconceptions, the distomer of a racemate is often considered inactive and of no consequence to pharmacological activity, an idea reinforced by the fact that resolution (i.e., separation) of racemates is economically disadvantageous. In the 1980s, Ariens and his associates (Ariens et al., 1983 Ariens, 1984, 1986) published a series of influential books and papers that showed the fallacy of this concept and pointed out the necessity of using pure enantiomers in therapy and research thankfully, this message has now been learned. 

The distomer should therefore be viewed as an impurity constituting 50% of the total amount of a drug—an impurity that in the majority of cases is by no means inert. Possible unwanted effects of a distomer are as follows ... 

However, there are instances in which the use of a racemate has advantages sometimes it is more potent than either of the enantiomers used separately (e.g., the antihistamine isothipendyl), or the distomer is converted into the eutomer in vivo (the anti-inflammatory... 

The more active isomer (where activity refers to binding affinity at a defined receptor) is designated the eutomer, the less active is the distomer. The ratio of activities is the eudismic ratio, and its logarithm, the eudismic index, is then proportional to the difference in binding free energy between the enantiomers. The eudismic index is a quantitative measure of chiral discrimination. 

Enantiomeric purity, measured as the enantiomeric excess (ee) of an isomer, is determined by the formula (% major isomer)—(% minor isomer). Thus, if a chiral drag is said to be or 50% ee, the composite mixture contains 75% of one enantiomer and 25% of the other. Enantioselectivity refers to the greater activity of one enantiomer over its minor image. Enantiospecificily is rarely observed and implies that one enantiomer possesses 100% of the observed activity in most cases it is more accurate to use the term highly enantioselective. The pharmacologically more active enantiomer is termed the eulomei and the less active enantiomer is referred to as tire distomer. 

Even more subtle effects arise for drug interactions of a non-chiral drug with a chiral one. Phenylbutazone is not chiral in itself but it can interact with a chiral drug, warfarin, to change the activity of the latter. Phenylbutazone inhibits the oxidative metabolism of the (S)-(-) form of warfarin, (which is five times more potent than the (/ )-(+) form) and thereby decreases its clearance. Conversely, phenylbutazone induces the enzymatic reduction of the (/ ) form thus increasing the clearance.93 Analysis of total warfarin may indicate little departure from normal pharmacokinetics, but the distribution of eutomer and distomer will have changed markedly. 

As can be seen from Figure 2, the (/ )-enantiomers (eutomers) of the silanols 3 and 7 show a significantly higher affinity for muscarinic M2 and M3 receptors than the corresponding (S)-antipodes (distomers). To the best of our knowledge, this is the first example of a biological discrimination between enantiomeric silicon compounds, with the silicon atom as the center of chirality. The stereoselectivity indices SI [SI = Kn S)/Kd(R) for sila-procyclidine (3) are 1.8 (M2) and 4.1 (M3), respectively. For sila-tricyclamol iodide... 

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