Stereospecific Taurine Conjugation of the trans-OH Metabolite (Active Metabolite) of CS-670, a New 2-Arylpropionic Acid Nonsteroidal Anti-inflammatory Drug, in Dogs

Abstract

CS-670, (±)-2-[4-(2-oxocyclohexylidenemethyl) phenyl] propionic acid, is a novel derivative of 2-arylpropionic acid non-steroidal anti-inflammatory drugs (profen NSAIDs). The major urinary metabolite of this drug from dogs was isolated and its chemical structure was determined by MS and NMR spectroscopy. The metabolite was identified as a taurine conjugate of the trans-OH form (trans-OH-taurine) which was first generated by stereoselective reduction of the double bond and the carbonyl function of the CS-670 molecule. The taurine conjugate was excreted in urine as the main metabolite, regardless of the optical configuration of CS-670 administered [(2R)-enantiomer : 47.2% of the dose, (2S)-enantiomer : 70.9% of the dose]. The trans-OH-taurine was hydrolyzed by refluxing it in 6N HCl without racemization. The released trans-OH was derivatized to diastereoamides with (+)-(R)-1-(1-naphthyl) ethylamine to examine the stereochemical properties of the 2-arylpropionic acid side chain. It was found that the configuration of the 2-carbon of the trans-OH-taurine was almost entirely (S). As the CoA thioesters are obligate intermediates for amino acid conjugation, the results suggest that the (2S)-enantiomer of the trans-OH metabolite serves as a substrate for canine acyl CoA ligase (EC 6.2.1.3) as well as the (2R)-enantiomer, but only the CoA thioester with a (2S)-configuration is a substrate for taurine N-acyl transferase. It is interesting to note that these results are not consistent with the chiral inversion mechanism by which the (2R)-enantiomers of profen NSAIDs are stereospecifically converted to CoA thioester intermediates.