Chiral inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs—II Racemization and hydrolysis of ( R)- and ( S)-ibuprofen-CoA thioesters

Abstract

The inversion of 2-arylpropionic acids (2-APAs) has become the subject of much attention. It is a unique reaction specific to this group of drugs. Inversion proceeds via stereoselective activation of the R-enantiomer to its CoA thioester whereby it is then racemized and hydrolysed to release free drug. The racemization and hydrolysis processes have been examined in this study using chemically synthesized CoA thioesters of the ibuprofen enantiomers and in vitro models employing rat liver homogenate and the mitochondrial and microsomal fractions as the source of the ‘racemase’ enzymes. Rat liver homogenate mediated the racemization and hydrolysis of both ( R)- and ( S)-ibuprofen-CoA thioesters. The rat liver mitochondrial fraction similarly mediated racemization and hydrolysis of both CoA thioesters. There was less racemase activity in the rat liver microsomal fraction and the data indicated that this fraction may contain two hydrolases which act separately on the ( R)- and ( S)-ibuprofen-CoA thioesters. The data are further evidence that the stereoselectivity of the CoA synthetase controls the overall stereoselectivity of inversion.