19340-33-1Relevant articles and documents
Mechanistic studies on metabolic chiral inversion of 4-(4-methylphenyl)-2-methylthiomethyl-4-oxobutanoic acid (KE-748), an active metabolite of the new anti-rheumatic agent 2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-298), in rats
Yoshida, Hideo,Kohno, Yoshiro,Endo, Hiromi,Yamaguchi, Jun-Ichi,Fukushima, Kiyomi,Suwa, Toshio,Hayashi, Masahiro
, p. 179 - 187 (1997)
The chiral inversion properties of 4-(4-methylphenyl)-2-methylthiomethyl-4-oxobutanoic acid (KE-748), an active metabolite of 2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-298), were compared with those of ibuprofen in rats. After administration of R(-)-[2α-2H]KE-748, S(+)-KE-748 was present in the rat plasma, and the deuterium atoms of the S(+)-enantiomer were almost all replaced by hydrogen atoms. After administration of S(+)-[2α-2H]KE-748, the deuterium content of S(+)-KE-748 in the plasma remained intact. In the in vitro study, using a cell-free system and rat liver homogenates, the chiral inversion of ibuprofen was apparent when both CoA and ATP were present; however, KE-748 was not inverted. In the study on isolated rat hepatocytes, the unidirectional chiral inversion from R(-)- to S(+)-enantiomer was observed for both ibuprofen and KE-748. When R(-)-ibuprofen was incubated with medium and long chain fatty acids (carbon chain length C6 to C16), using isolated hepatocytes, the chiral inversion decreased significantly. On the other hand, when R(-)-KE-748 was incubated with short and medium chain fatty acids (carbon chain length C3 to C8), chiral inversion was inhibited markedly. To induce hepatic microsomal long chain fatty acid CoA ligase, rats were treated with clofibric acid (CF rats). In both in vitro and in vivo experiments on CF rats, chiral inversion from R(-)- to S(+)-ibuprofen was enhanced significantly compared with that in controls, whereas the enhancement was not observed in the case of R(-)-KE-748. There was no influence of benzoic acid, a typical substrate on medium chain fatty acid CoA ligase in the mitochondrial matrix, on chiral inversion of R(-)-ibuprofen, using isolated hepatocytes. In contrast, the chiral inversion from R(-)- to S(+)-KE-748 was strongly inhibited in the presence of benzoic acid. These results indicate that chiral inversion of R(-)-KE-748 may proceed via formation of the CoA-thioester intermediate with loss of the 2α-methine proton, in a manner similar to that seen with R(-)-ibuprofen. However, the enzymes needed to form CoA-thioester of R(-)-KE-748 differ from those for R(-)-ibuprofen.
Enzyme-Inspired Chiral Secondary-Phosphine-Oxide Ligand with Dual Noncovalent Interactions for Asymmetric Hydrogenation
Chen, Caiyou,Zhang, Zhefan,Jin, Shicheng,Fan, Xiangru,Geng, Mingyu,Zhou, Yan,Wen, Songwei,Wang, Xinrui,Chung, Lung Wa,Dong, Xiu-Qin,Zhang, Xumu
supporting information, p. 6808 - 6812 (2017/06/06)
Inspired by the unique character of enzymes, we developed novel chiral SPO (secondary-phosphine-oxide) ligand (SPO-Wudaphos) which can enter into both ion pair and H-bond noncovalent interactions. The novel chiral SPO-Wudaphos exhibited excellent results
A practical procedure for the synthesis of Esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid, an antirheumatic agent. II
Noguchi, Toshiya,Onodera, Akira,Ito, Masato,Yoshida, Mamoru,Yokomori, Sadakazu
, p. 2657 - 2670 (2007/10/03)
An efficient large-scale synthesis of Esonarimod, (R,S)-2-acetylthio-methyl-4-(4-methylphenyl)-4-oxobutanoic acid (1), a new antirheumatic drug, was established. A small amount of water increased the yield of the Michael addition of thioacetic acid (4) to
