Proinflammatory mediators such as cytokines and NO play pivotal roles in various inflammatory diseases. To combat inflammatory
diseases successfully, regulation of proinflammatory mediator production ...would be a critical process. In the present study,
we investigated the in vitro effects of ethyl (6 R )-6- N -(2-chloro-4-fluorophenyl)sulfamoylcyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule cytokine production inhibitor,
and its mechanism of action. In RAW264.7 cells and mouse peritoneal macrophages, TAK-242 suppressed lipopolysaccharide (LPS)-induced
production of NO, tumor necrosis factor-α (TNF-α), and interleukin (IL)-6, with 50% inhibitory concentration (IC 50 ) of 1.1 to 11 nM. TAK-242 also suppressed the production of these cytokines from LPS-stimulated human peripheral blood mononuclear
cells (PBMCs) at IC 50 values from 11 to 33 nM. In addition, the inhibitory effects on the LPS-induced IL-6 and IL-12 production were similar in
human PBMCs, monocytes, and macrophages. TAK-242 inhibited mRNA expression of IL-6 and TNF-α induced by LPS and interferon-γ
in RAW264.7 cells. The phosphorylation of mitogen-activated protein kinases induced by LPS was also inhibited in a concentration-dependent
manner. However, TAK-242 did not antagonize the binding of LPS to the cells. It is noteworthy that TAK-242 suppressed the
cytokine production induced by Toll-like receptor (TLR) 4 ligands, but not by ligands for TLR2, -3, and -9. In addition, IL-1β-induced
IL-8 production from human PBMCs was not markedly affected by TAK-242. These data suggest that TAK-242 suppresses the production
of multiple cytokines by selectively inhibiting TLR4 intracellular signaling. Finally, TAK-242 is a novel small molecule TLR4
signaling inhibitor and could be a promising therapeutic agent for inflammatory diseases, whose pathogenesis involves TLR4.
Chemical modification has been performed on an orally bioavailable and potent CCR5 antagonist, sulfoxide compound 4, mainly focusing on replacement of the 6,7-fused 1-benzazepine nucleus. We ...designed, synthesized, and evaluated the biological activities of ring-expanded 6,8-, 6,9-, and 6,10-fused compounds containing S-sulfoxide moieties, which led to the discovery of 1-benzazocine and 1-benzazonine compounds that exhibited potent inhibitory activities (equivalent to compound 4) in a binding assay. In addition, 1-benzazocine compounds possessing the S-sulfoxide moiety (( S )-(−)-5a,b,d,e) showed greater potency than compound 4 in a fusion assay. From further investigation in a multi-round infection assay, it was found that 1-isobutyl-1-benzazocine compound ( S )-(−)-5b, containing the S-{(1-propyl-1H-imidazol)-5-ylmethyl}sulfinyl group, showed the most potent anti-HIV-1 activity (IC90 = 0.81 nM, in MOLT4/CCR5 cells). Compound ( S )-(−)-5b (TAK-652) also inhibited the replication of six macrophage-tropic (CCR5-using or R5) HIV-1 clinical isolates in peripheral blood mononuclear cells (PBMCs) (mean IC90 = 0.25 nM). It was also absorbed after oral administration in rats, dogs, and monkeys and was thus selected as a clinical candidate. The synthesis and biological activity of the 1-benzazocine compound ( S )-(−)-5b and its related derivatives are described.
Objective and design Toll-like receptor 4 (TLR4) plays important roles in the recognition of lipopolysaccharide (LPS) and the activation of inflammatory cascade. In this study, we evaluated the ...effect of TAK-242, a selective TLR4 signal transduction inhibitor, on acute lung injury (ALI). Materials and methods C57BL/6J mice were intravenously treated with TAK-242 15 min before the intratracheal administration of LPS or Pam3CSK4, a synthetic lipopeptide. Six hours after the challenge, bronchoalveolar lavage fluid was obtained for a differential cell count and the measurement of cytokine and myeloperoxidase levels. Lung permeability and nuclear factor-κB (NF-κB) DNA binding activity were also evaluated. Results TAK-242 effectively attenuated the neutrophil accumulation and activation in the lungs, the increase in lung permeability, production of inflammatory mediators, and NF-κB DNA-binding activity induced by the LPS challenge. In contrast, TAK-242 did not suppress inflammatory changes induced by Pam3CSK4. Conclusion TAK-242 may be a promising therapeutic agent for ALI, especially injuries associated with pneumonia caused by Gram-negative bacteria.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We incorporated various polar groups into previously described piperidine-4-carboxamide CCR5 antagonists to improve their metabolic stability in human hepatic microsomes. Introducing a carbamoyl ...group into the phenyl ring of the 4-benzylpiperidine moiety afforded the less lipophilic compound 5f, which possessed both high metabolic stability and good inhibitory activity of HIV-1 envelope-mediated membrane fusion (IC50 = 5.8 nM). Further optimization to increase potency led to the discovery of 1-acetyl-N-{3-4-(4-carbamoylbenzyl)piperidin-1-ylpropyl}-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide (5m, TAK-220), which showed high CCR5 binding affinity (IC50 = 3.5 nM) and potent inhibition of membrane fusion (IC50 = 0.42 nM), as well as good metabolic stability. Compound 5m strongly inhibited the replication of CCR5-using HIV-1 clinical isolates in human peripheral blood mononuclear cells (mean EC50 = 1.1 nM, EC90 = 13 nM) and exhibited a good pharmacokinetic profile in monkeys (BA = 29%). This compound has been chosen as a clinical candidate for further development.
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