Enzymatic inversion at saturated carbon: Nature and mechanism of the inversion of R(−) p-iso-butyl hydratropic acid

Stereoselective disposition of ibuprofen enantiomers in man.

“…In a study with benoxaprofen, f, was estimated to be approximately 50% (Bopp et al, 1979 A number of studies have considered the mechanism of the inversion reaction for ibuprofen (Hutt & Caldwell, 1983;Nakamura et al, 1980;Wechter et al, 1974). The prerequisite for inversion appears to be the highly stereoselective esterification of R(-)I to its coenzyme A thioester (Figure 2).…”

The metabolic chiral inversion of 2-arylpropionic acids—a novel route with pharmacological consequences

“…indicated retention of all 3 deuterium atoms. It would thus appear that the chiral inversion reaction of 2-(2-isopropylindan-S-y1) propionic acid does not involve formation of a methylene intermediate as proposed by Wechter et al (1974) since this would cause loss of deuterium from the a-methyl group. Upon administration of a-methine-dl-racemic IX, its metabolite S( +)-IXa was found to comprise an equimolar mixture of deuterated and protonated forms.…”

“…These workers postulated that the chiral inversion process involved formation of an acyl-CoA thioester, followed by dehydrogenation and formation of an a-methylene function via the enzymes of lipid metabolism and speculated on the existence of an R( -)-arylpropionic acid isomerase enzyme system, which exerted stereospecificity in the final reduction step (eqn 3). By comparison of the rates of disappearance of R( -)-d4-ibuprofen and R( -)-do-ibuprofen (rate do : rate do -2), the authors suggested that the dehydrogenation was the ratelimiting step (Wechter et al 1974).…”

“…The S(+)-enantiomer of ibuprofen was found to be excreted unchanged, in terms of configuration, and after administration of the racemate, 71% of the total amounts of both ibuprofen and metabolite VIa were present as the S(+)-enantiomers. The loss of two deuterium atoms from the metabolites of R( -)-d4-ibuprofen led Wechter et al (1974) to propose a mechanism for the chiral inversion process (see below). It was also noted, by comparison of the inversion rates of do and d4 R(-)-ibuprofen.…”

Physicochemical stability of solid dispersions of enantiomeric or racemic ibuprofen in stearic acid

“…This is due to the fact that the inactive R-(-)enantiomer can easily be converted in vivo to the active form. [6][7][8] Nevertheless, a certain quantity of R-enantiomer may be retained in adipose tissues and cause unwanted effects. Therefore, a reduction in the dosage of ibuprofen Chemical structure of (a) S-ibuprofen and (b) R-ibuprofen drawn from the corresponding X-ray crystallographic information files.…”