Enantioselective Uptake of BOF-4272, a Xanthine Oxidase Inhibitor with a Chiral Sulfoxide, by Isolated Rat Hepatocytes

Abstract

The structures of the S(-) and R(＋) enantiomers of BOF-4272 are shown on the left and right, respectively. The transport mechanisms of the enantiomers of BOF-4272, a new drug for the treatment of hyperuricemia, were studied using freshly prepared rat hepatocytes. BOF-4272 consists of S(-) and R(＋) enantiomers due to a chiral center in the sulfoxide moiety. The uptake of these BOF-4272 enantiomers by hepatocytes was found to be temperature and dose dependent. The temperature-dependent uptake of the S(-) and R(＋) enantiomers showed saturation kinetics. The K m values for the S(-) and R(＋) enantiomers were 59.3 and 25.7 mM, respectively, which was a signiˆcant diŠer-ence (p＜0.05). However, the maximal uptake rate was comparable for both enantiomers. Metabolic inhibitors such as antimycin, oligomycin, rotenone, carbonylcyanide m-chlorophenyl hydrazone, and carbonyl cyanide-p-(tri‰u-romethoxy)-phenylhydrazone signiˆcantly inhibited uptake of the R(＋) enantiomer, but had little eŠect on uptake of the S(-) enantiomer. Ouabain (an inhibitor of Na ＋ /K ＋ -ATPase) and p-nitrobenzylthioinosine (NBMPR, a nucleoside transporter inhibitor) showed no signiˆcant eŠects on the uptake of either enantiomer. Organic anions such as taurocholate and cholate reduced the uptake of both enantiomers. These results suggest that the hepatic uptake of both BOF-4272 enantiomers is not due to simple diŠusion but also involves carrier-mediated uptake. We suggest that the carrier-mediated uptake of BOF-4272 enantiomers includes both NBMPR-insensitive facilitated diŠusion and an active transport system in liver plasma membrane, and that the enantioselective uptake of BOF-4272 is due to diŠerences in a‹nity for the active transporter.

Pyrazolo[1,5-a][1,3,5]triazines (5-Aza-9-deazapurines): Synthesis and Biological Activity

“…118,119 The stereoselectivity was also observed for the pharmacokinetic parameters and biotransformation of BOF 4272. [123][124][125][126][127] Considering these facts, the asymmetric syntheses of BOF 4272 were developed. [128][129][130] It was reported that substituted 2,4-diaminopyrazolo[1,5-a] [1,3,5]triazines were able to inhibit type 2 cyclin-dependent kinase (CDK2), which are involved in the regulation of the cell cycle.…”

Six‐coordinated vanadium(IV) complexes with tridentate task‐specific ionic liquid Schiff base ligands: Synthesis, characterization and effect of ionic nature on catalytic activity

“…Optically active sulfoxides possess a wide range of biological activities, e.g. antimicrobial properties, inhibition of biosynthesis of uric acid and gastric acid secretion or regulation of cholesterol catabolism …”

“…[4,8] Optically active sulfoxides possess a wide range of biological activities, e.g. antimicrobial properties, [9] inhibition of biosynthesis of uric acid [10] and gastric acid secretion [11] or regulation of cholesterol catabolism. [12] Ionic liquids have not only become increasingly popular as reaction and extraction media in research and development, but also they have widely been promoted as 'green solvents', which are regarded as powerful alternatives to volatile organic compounds in the field of organic synthesis.…”

Oxidation of sulfides to chiral sulfoxides using Schiff base-vanadium (IV) complexes

“…The drug inhibits the biosynthesis of uric acid by blocking xanthine oxidase. 19 Unge and co-workers have reported the asymmetric synthesis of esomeprazole, a drug containing a chiral sulfoxide group known to inhibit gastric acid secretion. 20a Padmanahan and co-workers from Cambridge Neuro Science have reported the asymmetric synthesis of a sulfoxide containing a guanidine portion that is an active N-methyl-D-aspartate ion-channel blocker.…”