Ethyl (6
R)-6-
N-(2-chloro-4-fluorophenyl)sulfamoylcyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule that selectively inhibits Toll-like receptor 4-mediated signaling, inhibits various ...kinds of inflammatory mediators such as nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-10, macrophage inhibitory protein (MIP)-2 and prostaglandin E
2 from lipopolysaccharide (LPS)-stimulated macrophages. The effects of TAK-242 were evaluated in a mouse model of endotoxin shock. Intravenous administration of TAK-242 to mice 1 h before LPS challenge dose-dependently inhibited LPS-induced increases in serum levels of TNF-α, IL-1β, IL-6, IL-10, MIP-2, and NO metabolites. TAK-242 protected mice from LPS-induced lethality in a similar dose-dependent manner, and rescued 100% of mice at a dose of 1 mg/kg. Interestingly, TAK-242 worked quickly, and showed beneficial effects even when administered after LPS challenge. Even though increases in serum levels of IL-6 and hypothermia were already evident 2 h after LPS challenge, TAK-242 administration inhibited further increase in IL-6 levels and decrease in body temperature. LPS-induced increases in serum levels of organ dysfunction markers, such as alanine aminotransferase, total bilirubin, and blood urea nitrogen, were also significantly suppressed by post-treatment as well as pre-treatment. Furthermore, administration of 3 mg/kg TAK-242 significantly increased survival of mice, even when given 4 h after LPS challenge. These results suggest that TAK-242 protects mice against LPS-induced lethality by inhibiting production of multiple cytokines and NO. TAK-242 has a quick onset of action and provides significant benefits by post-treatment, suggesting that it may be a promising drug candidate for the treatment of sepsis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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.
Sepsis is characterized by an excessive host response to infection. Toll-like receptors (TLRs) are essential for triggering this type of host immune response. Toll-like receptor 4 mediates ...recognition of LPS from gram-negative bacteria and is an important initiator of sepsis. In the present study, we evaluated the efficacy of TAK-242, a novel TLR4 signal transduction inhibitor, in a murine cecal ligation and puncture (CLP) model. Treatment with TAK-242 (10 mg/kg i.v.) in combination with imipenem (1 mg/kg s.c.) 1 h after CLP significantly increased the survival rates of mice from 17% to 50% (P ≤ 0.01) and suppressed CLP-induced increases in serum levels of IL-1beta, IL-6, IL-10, and macrophage inflammatory protein 2 by 64%, 73%, 79%, and 81%, respectively (P ≤ 0.025). Additionally, coadministration of TAK-242 with imipenem after CLP significantly inhibited CLP-induced decreases in blood platelet counts by 37% (P ≤ 0.025) and increases in serum levels of alanine aminotransferase by 32% (P ≤ 0.025) and blood urea nitrogen by 43% (P ≤ 0.025). TAK-242 at a dose of 10 mg/kg had no effect on bacterial counts in blood, suggesting that it does not affect blood bacteria spread. These results indicate that TAK-242 shows therapeutic effects in murine polymicrobial sepsis, and it may be a potential therapeutic agent for the treatment of sepsis.
The β -chemokine receptor CCR5 is considered to be an attractive target for inhibition of macrophage-tropic (CCR5-using or R5) HIV-1 replication because individuals having a nonfunctional receptor (a ...homozygous 32-bp deletion in the CCR5 coding region) are apparently normal but resistant to infection with R5 HIV-1. In this study, we found that TAK-779, a nonpeptide compound with a small molecular weight (Mr 531.13), antagonized the binding of RANTES (regulated on activation, normal T cell expressed and secreted) to CCR5-expressing Chinese hamster ovary cells and blocked CCR5-mediated Ca2+ signaling at nanomolar concentrations. The inhibition of β -chemokine receptors by TAK-779 appeared to be specific to CCR5 because the compound antagonized CCR2b to a lesser extent but did not affect CCR1, CCR3, or CCR4. Consequently, TAK-779 displayed highly potent and selective inhibition of R5 HIV-1 replication without showing any cytotoxicity to the host cells. The compound inhibited the replication of R5 HIV-1 clinical isolates as well as a laboratory strain at a concentration of 1.6-3.7 nM in peripheral blood mononuclear cells, though it was totally inactive against T-cell line-tropic (CXCR4-using or X4) HIV-1.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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.
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In order to develop orally active CCR5 antagonists, 1-propyl- or 1-isobutyl-1-benzazepine derivatives containing a sulfoxide moiety have been designed, synthesized, and evaluated for ...their biological activities. Sulfoxide compounds containing a 2-pyridyl group were first investigated, which led to discovering that the presence of a methylene group between the sulfoxide moiety and 2-pyridyl group was necessary for increased inhibitory activity in a binding assay. After further chemical modification, it was found that replacement of the pyridyl group with an imidazolyl or 1,2,4-triazolyl group enhanced activity in the binding assay and that
S-sulfoxide compounds were more active than
R-isomers. Particularly, compounds (
S
)-
4r, (
S
)-
4s, and (
S
)-
4w exhibited highly potent CCR5 antagonistic activities (IC
50
=
1.9, 1.7, 1.6
nM, respectively) and inhibitory effects (IC
50
=
1.0, 2.8, 7.7
nM, respectively) in the HIV-1 envelope mediated membrane fusion assay, together with good pharmacokinetic properties in rats. In addition, we established the synthesis of (
S
)-
4r and (
S
)-
4w by asymmetric oxidation with titanium-(
S)-(−)-1,1′-bi-2-naphthol complex.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
TAK-242, a small-molecule antisepsis agent, has shown to suppress lipopolysaccharide (LPS)-induced inflammation. In this study, we demonstrate that TAK-242 is a selective inhibitor of Toll-like ...receptor (TLR)-4 signaling. TAK-242 almost completely suppressed production of nitric oxide (NO) or tumor necrosis factor (TNF)-α induced by a TLR4-specific ligand, ultra-pure LPS, in mouse RAW264.7, human U-937 and P31/FUJ cells, whereas this agent showed little effect on other TLR ligands, Pam
3CSK
4 (TLR1/2), peptidoglycan (TLR2/6), double strand RNA (TLR3), R-848 (TLR7) and CpG oligonucleotide (TLR9). Furthermore, TAK-242 potently inhibited nuclear factor (NF)-κB activation induced by ultra-pure LPS in HEK293 cells transiently expressing TLR4 and co-receptors, myeloid differentiation protein-2 (MD2) and CD14, whereas this agent showed little effect on other TLRs, TLR1/2, TLR2/6, TLR3, TLR5, TLR7 and TLR9. TAK-242 also inhibited ligand-independent NF-κB activation resulting from over-expression of TLR4. Although chimera receptors, which are consist of the extracellular domain of CD4 and the intracellular domain of human or mouse TLR4, showed constitutive NF-κB activation, TAK-242 potently inhibited the signaling from CD4-TLR4 chimera receptors. In contrast, the NF-κB activation mediated by TLR4 adaptors, myeloid differentiation factor 88 (MyD88), TIR-associated protein (TIRAP), Toll/IL-1R homology (TIR)-domain-containing adaptor protein-inducing interferon-β (TRIF) or TRIF-related adaptor molecule (TRAM) was not affected by TAK-242. TAK-242 is therefore a selective inhibitor of signaling from the intracellular domain of TLR4 and represents a novel therapeutic approach to the treatment of TLR4-mediated diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
TAK-599 is a water-soluble prodrug of a cephalosporin compound, T-91825. In vitro and in vivo antibacterial activities of T-91825 and TAK-599, respectively, were examined. T-91825 was active against ...both gram-positive and gram-negative bacteria, unlike vancomycin and linezolid, which are inactive against gram-negative bacteria. The 90% minimum inhibitory concentration of T-91825 against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) was 2μg/ml. This activity was comparable to those of vancomycin, linezolid, teicoplanin, and arbekacin. T-91825 was similarly active against vancomycin-intermediate S. aureus. In a time-kill study, T- 91825 showed more rapid and distinct decrease of viable cells of two MRSA strains than did vancomycin and linezolid in vitro. The effect of TAK-599 against systemic infection caused by clinical isolates of MRSA in mice was comparable or superior to that of vancomycin, linezolid, teicoplanin, and arbekacin. In addition, TAK-599 at a dose of 20mg/kg significantly decreased bacterial counts in lungs of mice in an experimental pneumonia model caused by MRSA in which vancomycin and linezolid were totally ineffective at the same dose. These results suggest the usefulness of TAK-599 in the treatment of MRSA infections in humans.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UL, UM, UPCLJ, UPUK, VKSCE, ZAGLJ
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