Inversion of arylpropionic acids

Unidirectional chiral inversion of arylpropionic acids (profens)... 

Hutt A.J., Kooloobandi A. Hanlon GW. (1993) Microbial metabolism of 2-arylpropionic acids Chiral inversion ofibuprofen and 2-phenylpropionic acid. Chirality, 5, 596-601. 

Many nonsteroidal anti-inflammatory drugs (NSAIDs) are substituted 2-arylpropionic acids. Most NSAIDs also have a chiral carbon next to the carboxylate and are administered as a racemic mixture of the two enantiomers. In general, the (S)-enantiomcr is responsible for most of the antiinflammatory activity of these agents. It was found that the (/ -enantiomer is converted to the (S)-enantiomer but the reverse does not occur (23). As with amino acid conjugation, the pathway involves reaction with ATP to form an AMP ester, which is, in turn, converted to a Co-A ester, and it is the Co-A ester that undergoes chiral inversion (Fig. 7.14). Substrates include ibuprofen, naproxen, and fenoprofen. 

Hutt, A.J. Caldwell, J., The metabolic chiral inversion of 2-arylpropionic acids A novel route with pharmacological consequences J. Pharm. Pharmacol. 1983, 35, 693-704. 

J. Caldwell, A. J. Hutt, and S. Foumel-Gigleux, The metabolic chiral inversion and dispositional enantioselecHvity of the 2-arylpropionic acids and their biological consequences," Biochem. Pharmacol., 37 105-114 (1988). 

It is usual in humans for the S(+)-enantiomer of 2-arylpropionic acids to predominate in plasma and for the S(- -)- to R(-)-enantiomeric ratio of plasma concentrations to increase with time after administration of the racemate, which is often attributed to metabolic inversion of the chiral center of the R( )-enantiomers to their S(- -)-antipodes. ° In humans, the S(- -)-enantiomer is generally eliminated more slowly than is the R( )-enantiomer. The extent of chiral inversion of fenoprofen, which has been attributed to the differential rate of formation of the CoA-thioester by hepatic microsomes, varies widely among species. It has been estimated to be 90% in dogs, 80% in sheep, 73% in rabbits, 60% in humans, 42% in rats,f and 38% in horses. ... 

Various arylpropionic acids show similar specificity. For most, if not all, the (5) enantiomer is the pharmacologically active one, whereas the R) enantiomer is usually much less active, although the ratio of iS)/ R) activity varies from drug to drug (and species to species). Only one of these drugs, however, is administered as the separated (S) enantiomer (naproxen, Naprosyn ). Normally these drugs are considered safe, and one cannot readily differentiate between the relative activities of the (S) and (R) forms because the in vivo half-life is very short, typically one or two hours. In patients with impaired renal function, where clearance is much slower, however, problems can arise. From in vivo studies of ibuprofen, it was established that the (S)-(-l-) isomer was responsible for antiinflammatory activity. In vivo, however, the (/ )-(-) isomer may become active because there is stereoselective inversion from R) to (S) (but not from 5 to R) in vivo with a half-life of about two hours. This inversion apparently proceeds by stereoselective formation of the coenzyme A (CoA) ester of the (f )-(-)-arylpropionic acid, followed by epimerization and release of the (S)-(+)-enantiomer. This epimerization is observed in vivo before the oxidative metabolism. Such inversion from (R) to (S) in vivo is also known for fenoprofen and benoxa-profen, and is expected to occur for most of the drugs of this series. ... 

It is assumed that the coenzyme A ester (CoA-ester) of the R(-)-enantiomer acts as a substrate for the fatty acid deshydrogenase, thus eliminating the chiral center. The next step may, or may not, take place, depending whether or not the CoA-ester must be transferred to an acyl-carrier protein or another site in the fatty acid synthetase system, so that a stereoselective reduction by an enoykeductase can take place. Thus the nature of X is unknown. Similar epimerization reactions were also described for some other arylpropionic acids such as benoxaprofen, carprofen, and isopropyl-indanyl-propionic acid. ° It was demonstrated that the configural inversion does not take place in the liver, and that the responsible enzyme, R-(-)-aryIpro-... 

Figure 14 Mechanism of the metabolic chiral inversion of 2-arylpropionic acid NSAIDs.

Arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drugs (NSAlDs) provide one of the most studied illustrated pharmaceutical examples of inversion by conjugation through a coenzyme A (CoA) thioester intermediate. It is also possible that bioinversion of xenobiotics proceed through other conjugation mechanisms such as glutathione [1 ]. 

The 2-arylpropionic acid class (2-APA) of nonsteroidal anti-inflammatory drugs (NSAlDs) (Table 1) is characterized by each member having an asymmetric carbon a to the carboxylic acid moiety. The R-enantiomer of this chiral center of some 2-APAs may undergo an in vivo inversion to the S-enantiomer. This inversion process varies substantially between the different members of this class and also varies between species of animal studied. The members of this class that are currently in clinical use include ibuprofen, ketoprofen, tiaprofenic acid, fenoprofen, and flurbiprofen. The majority are marketed as racemates. Naproxen and its sodium salt are internationally marketed as the pure S(-l-)-enantiomer, while ibuprofen and ketoprofen are now marketed in several European countries as the stereochemically pure S(-l-)-enantiomer. 

Chen, C.S. Chen, T. Shieh, W.R. Metabolic stereoisomeric inversion of 2-arylpropionic acids. On the mechanism of ibuprofen epimerization in rats. Biochemica Biophysica Acta 1990, 1033, 1-6. 

Thomason, M.J. Rhys-Williams, W. Lloyd, A.W. Hanlon, G.W. The stereo inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs and structurally related compounds by Verticillium lecanii. J. Appl. Microbiol. 

Mayer, J.M. Bartalucci, C. Maitre, J. Testa, B. Metabolic chiral inversion of anti-inflammatory 2-arylpropionates lack of reaction in liver homogenates, and study of methine proton acidity. Xenobiotica 1988, 18, 533-543. 

---