Synthesis and structure–activity relationships of novel IKK-β inhibitors. Part 3: Orally active anti-inflammatory agents

Murata, Toshiki; Shimada, Mitsuyuki; Sakakibara, Satoshi; Yoshino, T.; Masuda, Tsutomu; Shintani, Takuya; Sato, Hiroki; Koriyama, Yuji; Fukushima, Keiko; Nunami, Noriko; Yamauchi, Megumi; Fuchikami, Kinji; Kono, Hiroshi; Watanabe, Akihiko; Ziegelbauer, Karl; Bacon, Kevin B.; Lowinger, Timothy B.

doi:10.1016/j.bmcl.2004.05.041

Cited by 120 publications

(58 citation statements)

References 9 publications

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“…[29][30][31][32] The identification of a 2-amino-3-cyano-4-aryl-6-(2-hydroxyphenyl)pyridine analog as a lead compound by highthroughput screening assay and subsequent chemical optimization have led to the identification of 2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-piperadin-4-yl nicotinonitrile (ACHP) as a potent and selective IKKb inhibitor. [33][34][35] In the course of in vitro screening of a series of anilinopyrimidine derivatives and ATP competitors for their inhibitory effects on a constitutively active version of IKKb in which two serine residues within the activation loop of the catalytic domain are replaced with glutamic acids, AS602868 was identified to be a potent, reversible and ATP-competitive IKKb inhibitor, 36,37 and has been thus far used in various cell Chemical biology of inflammatory cytokine signaling T Kataoka types and animal models. In addition to the ATP-competitive types of IKKb inhibitors described above, 4-(2¢-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline (BMS-345541) was identified as a highly selective IKKb inhibitor that binds to an allosteric binding site, by means of an in vitro kinase assay.…”

Section: Synthetic Ikk Inhibitorsmentioning

confidence: 99%

Chemical biology of inflammatory cytokine signaling

Kataoka

2009

J Antibiot

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Pro-inflammatory cytokines, such as tumor necrosis factor-a and interleukin-1, trigger the signal transduction pathway leading to the activation of the transcription factor, nuclear factor-jB (NF-jB). NF-jB induces a large number of target genes involved in many biological processes, such as inflammation, immunity, cell survival, cell death and carcinogenesis. As therapeutic agents for inflammatory diseases and cancer, as well as bioprobes for the characterization of intracellular biological response and cell function, a large number of natural and synthetic small molecules have been identified to inhibit the activation of the NF-jB signaling pathway. This review focuses on recent progress in the identification and biological properties of small molecules targeting the NF-jB signaling pathway induced by pro-inflammatory cytokines.

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Section: Synthetic Ikk Inhibitorsmentioning

confidence: 99%

Chemical biology of inflammatory cytokine signaling

Kataoka

2009

J Antibiot

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“…The 50% inhibitory concentrations for IKK-␤ and IKK-␣ are 8.5 and 250 nmol/liter, respectively, measured by in vitro kinase assays, and those for other kinases, such as IKK-␥, Syk, and mitogen-activated protein kinase kinase kinase 4, were greater than 20 mol/liter (42). ACHP also showed good aqueous solubility and cell permeability, thus demonstrating high bioavailability in mice and rats (43).…”

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confidence: 94%

“…ACHP was found on a massive screening to have specific inhibitory action on IKK-␤ and IKK-␣ (42,43). The 50% inhibitory concentrations for IKK-␤ and IKK-␣ are 8.5 and 250 nmol/liter, respectively, measured by in vitro kinase assays, and those for other kinases, such as IKK-␥, Syk, and mitogen-activated protein kinase kinase kinase 4, were greater than 20 mol/liter (42).…”

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confidence: 99%

Inhibition of Human Immunodeficiency Virus Type 1 Replication in Latently Infected Cells by a Novel IκB Kinase Inhibitor

Victoriano

Asamitsu

Hibi

et al. 2006

Antimicrob Agents Chemother

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“…Among these compounds, ACHP exhibited the highest selectivity for IKKh and IKKa (IC 50 values for IKKh and IKKa are 8.5 and 250 nmol/L, respectively, measured by in vitro kinase assays) over other kinases such as IKK3, Syk, and mitogen-activated protein kinase kinase kinase 4 (IC 50 > 20 Amol/L for these kinases; ref. 22). In addition, ACHP showed good aqueous solubility and cellpermeability, thus demonstrating a very high oral bioavailability in mice and rats.…”

Section: Introductionmentioning

confidence: 99%

Growth Inhibition of Multiple Myeloma Cells by a Novel IκB Kinase Inhibitor

Sanda

Iida²,

Ogura³

et al. 2005

Clinical Cancer Research

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Involvement of nuclear factor-KB (NF-KB) in cell survival and proliferation of multiple myeloma has been well established. In this study we observed that NF-KB is constitutively activated in all human myeloma cell lines, thus confirming the previous studies. In addition, we found the phosphorylation of p65 subunit of NF-KB in addition to the phosphorylation of IKBA and the activation of NF-KB DNA binding and that various target genes of NF-KB including bcl-x L , XIAP, c-IAP1, cyclin D1, and IL-6 are up-regulated. We then examined the effect of a novel IKB kinase inhibitor, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile (ACHP). When myeloma cells were treated with ACHP, the cell growth was efficiently inhibited with IC 50 values ranging from 18 to 35 Mmol/L concomitantly with inhibition of the phosphorylation of IKBA/p65 and NF-KB DNA-binding, down-regulation of the NF-KB target genes, and induction of apoptosis. In addition, we observed the treatment of ACHP augmented the cytotoxic effects of vincristine and melphalan (L-phenylalanine mustard), conventional antimyeloma drugs. These findings indicate that IKB kinase inhibitors such as ACHP can sensitize myeloma cells to the cytotoxic effects of chemotherapeutic agents by blocking the antiapoptotic nature of myeloma cells endowed by the constitutive activation of NF-KB.

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Synthesis and structure–activity relationships of novel IKK-β inhibitors. Part 3: Orally active anti-inflammatory agents

Cited by 120 publications

References 9 publications

Chemical biology of inflammatory cytokine signaling

Chemical biology of inflammatory cytokine signaling

Inhibition of Human Immunodeficiency Virus Type 1 Replication in Latently Infected Cells by a Novel IκB Kinase Inhibitor

Growth Inhibition of Multiple Myeloma Cells by a Novel IκB Kinase Inhibitor

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