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Chemical Compound Review

Esonarimod     2-(ethanoylsulfanylmethyl)-4- (4...

Synonyms: KE-298, CHEMBL2003782, KE 298, AC1L2T05, Tox21_113282, ...
 
 
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Disease relevance of Esonarimod

  • KE-298 also significantly inhibited the delayed-type hypersensitivity (DTH) response to type II collagen, but did not affect the production of anti-type II collagen IgG antibody in arthritic mice [1].
  • In the present study, we examined the effects of D-penicillamine (D-Pc), 2-acetylthiomethyl-3-(4-methyl-benzoyl)propionic acid (KE-298) and dexamethasone (Dex) on dextran bead-induced lung granulomas in mice [2].
 

High impact information on Esonarimod

  • KE-298 may prevent this process by down-regulating MT1-MMP expression [3].
  • RESULTS: KE-298 and KE-758 suppressed NO production by LPS activated RAW264.7 cells by inhibiting iNOS gene expression [4].
  • The biotransformation of esonarimod (KE-298) [(+/-)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid], a new antirheumatic drug, was investigated in rats [5].
  • Identification of rat urinary and biliary metabolites of esonarimod, a novel antirheumatic drug, using liquid chromatography/electrospray ionization tandem mass spectrometry with postcolumn addition of 2-(2-methoxyethoxy)ethanol, a signal-enhancing modifier [5].
  • 5. The present results suggest that the S-oxidation of S-methyl esonarimod reflects FMO5 activity in the human liver because the recombinant FMO5 data match well with the human liver microsomal experiments [6].
 

Biological context of Esonarimod

  • These results revealed that the stereoselective pharmacokinetics of KE-298 in rats might be due to enantiomeric differences in binding to plasma albumin [7].
  • These results suggested that the stereoselective plasma levels in KE-298 and its metabolites were closely related to enantiomeric differences in protein binding attributed to quantitative differences in binding to albumin rather than to the different binding sites [8].
  • Displacement studies revealed that the (+)-(S) and (-)-(R)- enantiomers of KE-298 and their metabolites bound to the warfarin binding site on rat serum albumin [8].
  • Apoptosis was not obvious in resting T cells and was not augmented by KE-298 [9].
 

Anatomical context of Esonarimod

  • We examined in this study whether the newly developed disease-modifying antirheumatic drug (DMARD) 2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-298) augments activation-induced T cell death [9].
  • During incubation with isolated rat hepatocytes in vitro, the metabolic rates of KE-298 enantiomers were not significantly different [7].
  • KE-758, an active metabolite of the new anti-rheumatic drug KE-298, suppresses production of tumor necrosis factor-alpha and interleukin-1 beta in THP-1, a human monocyte cell line [10].
  • The objective of the present study was to clarify the effects of KE-298 against synovium functions, using rheumatoid arthritis synoviocytes [11].
  • KE-298 (10-100 microg/ml) and KE-758 (10-100 microg/ml) as well as a high concentration of NAC (10mM) dose-dependently inhibited the secretion of TRX by THP-1 and Jurkat cells [12].
 

Associations of Esonarimod with other chemical compounds

  • Peripheral blood (PB) T cells, isolated from healthy donors, were activated by incubation with interleukin-2 (IL-2) followed by further culture with 12-0-tetradecanoyl phorbol 13-acetate (PMA) and ionomycin in the presence or absence of KE-298 [9].
 

Gene context of Esonarimod

  • Suppressive effects of the new antirheumatic drug KE-298 on TNF alpha-induced production of matrix metalloproteinases but not of tissue inhibitor-1 of metalloproteinases in human rheumatoid synoviocytes [11].
  • In a phase II study of rheumatoid arthritis patients, ingestion of KE-298 led to significant improvements in the Lansbury index [11].
  • These results suggest that the inhibitory effect of KE-298 on MCP-1 and RANTES production might partly explain its efficacy in rats with adjuvant-induced arthritis and in patients with RA [13].
  • KE-298 blocked this IL-1beta-induced pro-MMP-2 activation and MT1-MMP expression, but did not affect IL-1beta-induced tissue inhibitor of metalloproteinase-2 (TIMP-2) secretion from rheumatoid synovial cells [3].
  • In summary, at appropriate dosages, KE-298 inhibited CIA and TNF-alpha production in mice [1].
 

Analytical, diagnostic and therapeutic context of Esonarimod

  • The levels of unchanged KE-298 in plasma after oral administration of (+)-(S)-KE-298 to rats were lower than those of (-)-(R)-KE-298, whereas the levels of M-1 and M-2 after administration of (+)-(S)-KE-298 were higher than after (-)-(R)-KE-298 [8].
  • At doses of 50 and 100 mg/kg, however, KE-298 inhibited the severity and development of the collagen-induced arthritis index, the progression of foot pad swelling, bone damage and histopathological changes [1].
  • KE-298 is a novel antirheumatic drug which suppresses various animal models of arthritis by inhibiting the production of inflammatory cytokines [11].
  • RT-PCR analysis indicated that the suppressive effects of KE-298 and KE-758 on TRX secretion could be partly explained by the inhibition of TRX mRNA expression [12].

References

  1. Effect of KE-298 on experimental arthritis in mice. Nagai, H., Takaoka, Y., Mori, H., Kawada, K. Pharmacology (1996) [Pubmed]
  2. Suppression of pulmonary granulomatous inflammation by immunomodulating agents. Hashimoto, M., Kobayashi, K., Yamagata, N., Katsura, T., Sugihara, S., Iwabuchi, H., Kasama, T., Kasahara, K., Takahashi, T., Takeshita, K. Agents Actions (1992) [Pubmed]
  3. Expression of membrane-type 1 matrix metalloproteinase in rheumatoid synovial cells. Honda, S., Migita, K., Hirai, Y., Origuchi, T., Yamasaki, S., Kamachi, M., Shibatomi, K., Fukuda, T., Kita, M., Hida, A., Ida, H., Aoyagi, T., Kawakami, A., Kawabe, Y., Oizumi, K., Eguchi, K. Clin. Exp. Immunol. (2001) [Pubmed]
  4. KE-298 and its active metabolite KE-758 suppress nitric oxide production by murine macrophage cells and peritoneal cells from rats with adjuvant induced arthritis. Inoue, T., Hamada, Y., Takeshita, K., Fukushima, K., Higaki, M. J. Rheumatol. (2001) [Pubmed]
  5. Identification of rat urinary and biliary metabolites of esonarimod, a novel antirheumatic drug, using liquid chromatography/electrospray ionization tandem mass spectrometry with postcolumn addition of 2-(2-methoxyethoxy)ethanol, a signal-enhancing modifier. Yamaguchi, J., Ohmichi, M., Hasegawa, M., Yoshida, H., Ogawa, N., Higuchi, S. Drug Metab. Dispos. (2001) [Pubmed]
  6. S-oxidation of S-methyl-esonarimod by flavin-containing monooxygenases in human liver microsomes. Ohmi, N., Yoshida, H., Endo, H., Hasegawa, M., Akimoto, M., Higuchi, S. Xenobiotica (2003) [Pubmed]
  7. Stereoselective pharmacokinetics of [14C]-labeled KE-298, a new anti-rheumatic drug, in rats. Yoshida, H., Kohno, Y., Endo, H., Hasegawa, M., Suwa, T. Chirality. (1996) [Pubmed]
  8. Stereoselective disposition and chiral inversion of KE-298, a new antirheumatic drug, in rats. Yoshida, H., Kohno, Y., Endo, H., Ohmi, N., Fukushima, K., Suwa, T., Hayashi, M. Chirality. (1997) [Pubmed]
  9. New disease-modifying antirheumatic drug 2 acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-298) selectively augments activation-induced T cell death. Urayama, S., Kawakami, A., Nakashima, T., Yamasaki, S., Hida, A., Ida, H., Kamachi, M., Nakamura, H., Origuchi, T., Migita, K., Kawabe, Y., Eguchi, K. J. Lab. Clin. Med. (2001) [Pubmed]
  10. KE-758, an active metabolite of the new anti-rheumatic drug KE-298, suppresses production of tumor necrosis factor-alpha and interleukin-1 beta in THP-1, a human monocyte cell line. Sugimoto, M., Inoue, T., Yamashita, M., Takeshita, K., Nakaike, S. Drugs under experimental and clinical research. (2002) [Pubmed]
  11. Suppressive effects of the new antirheumatic drug KE-298 on TNF alpha-induced production of matrix metalloproteinases but not of tissue inhibitor-1 of metalloproteinases in human rheumatoid synoviocytes. Takahashi, S., Inoue, T., Higaki, M., Mizushima, Y. Drugs under experimental and clinical research. (1998) [Pubmed]
  12. Effects of a new anti-rheumatic drug KE-298 and its active metabolite: KE-758 on secretion of thioredoxin and on the level of intracellular glutathione in human monocytes and T cells. Sugimoto, M., Inoue, T., Takeshita, K., Nakamura, H., Yodoi, J. Mol. Immunol. (2002) [Pubmed]
  13. The new antirheumatic drug KE-298 suppresses monocyte chemoattractant protein (MCP)-1 and RANTES production in rats with adjuvant-induced arthritis and in IL-1beta-stimulated synoviocytes of patients with rheumatoid arthritis. Inoue, T., Yamashita, M., Higaki, M. Rheumatol. Int. (2001) [Pubmed]
 
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