Synthesis and structure–activity relationship of imidazo(1,2-a)thieno(3,2-e)pyrazines as IKK-β inhibitors

Belema, Makonen; Bunker, Amy; Nguyen, Van; Beaulieu, Françis; Ouellet, Catherine; Qiu, Yuping; Zhang, Yunhui; Martel, Alain; Burke, James R.; McIntyre, Kim W.; Pattoli, Mark A.; Daloisio, Connie; Gillooly, Kathleen M.; Clarke, Wendy; Brassil, Patrick; Zusi, F. Christopher; Vyas, Dolatrai M.

doi:10.1016/j.bmcl.2007.05.031

Cited by 36 publications

(20 citation statements)

References 16 publications

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“…38 Further structure-activity relationship studies of BMS-345541 as a structural lead have recently revealed that its tetracycline analogs and imidazo(1,2-a)thieno(3,2-e) pyrazines are more potent IKKb inhibitors. 39,40 As a different approach to the development of IKKb inhibitors, the molecular structure of N-(3,5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxybenzamide (IMD-0354) was designed by analyzing the binding mode of aspirin to IKKb after the construction of the three-dimensional structure of a kinase domain of IKKb by homology modeling with protein kinase A as a template, and the estimation of the structure of active IKKb by referring to a model of IKK regulation. 41,42 The phase I clinical trial of topical formulation of IMD-0354 for treatment of atopic dermatitis has been successfully completed.…”

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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“…1, ultimately derived from a medicinal chemistry effort around BMS-345541 Belema et al, 2007;Kempson et al, 2009a,b). In the present report, we provide a detailed investigation of the pharmacology of BMS-066 in rodent models of experimental arthritis.…”

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confidence: 99%

Periodic, Partial Inhibition of IκB Kinase β-Mediated Signaling Yields Therapeutic Benefit in Preclinical Models of Rheumatoid Arthritis

Gillooly¹,

Pattoli²,

Taylor³

et al. 2009

J Pharmacol Exp Ther

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We have previously shown that inhibitors of IB kinase ␤ (IKK␤), including 4(2Ј-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline (BMS-345541), are efficacious against experimental arthritis in rodents. In our efforts to identify an analog as a clinical candidate for the treatment of autoimmune and inflammatory disorders, we have discovered the potent and highly selective IKK␤ inhibitor 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo [4,5-d]pyrrolo [2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066). Investigations of its pharmacology in rodent models of experimental arthritis showed that BMS-066 at doses of 5 and 10 mg/kg once daily was effective at protecting rats against adjuvant-induced arthritis, despite showing only weak inhibition at 10 mg/kg against a pharmacodymanic model of tumor necrosis factor ␣ production in rats challenged with lipopolysaccharide. The duration of exposure in rats indicated that just 6 to 9 h of coverage per day of the concentration necessary to inhibit IKK␤ by 50% in vivo was necessary for protection against arthritis. Similar findings were observed in the mouse collagen-induced arthritis model, with efficacy observed at a dose providing only 6 h of coverage per day of the concentration necessary to inhibit IKK␤ by 50%. This finding probably results from the cumulative effect on multiple cellular mechanisms that contribute to autoimmunity and joint destruction, because BMS-066 was shown to inhibit a broad spectrum of activities such as T cell proliferation, B cell function, cytokine and interleukin secretion from monocytes, T H 17 cell function and regulation, and osteoclastogenesis. Thus, only partial and transient inhibition of IKK␤ is sufficient to yield dramatic benefit in vivo, and this understanding will be important in the clinical development of IKK␤ inhibitors.The multisubunit IB kinase (IKK) complex is essential in transducing the signal-inducible activation of the transcription factor NF-B in response to proinflammatory stimuli. In the "canonical" pathway of NF-B activation, the IKK complex catalyzes the phosphorylation of IB proteins at specific serine residues, which triggers a subsequent ubiquitination and proteolysis of IB, leaving NF-B free to translocate to the nucleus (Ghosh and Karin, 2002). This multisubunit IKK complex is composed of two catalytic subunits, termed IKK␣ and IKK␤, and a regulatory subunit termed NEMO (or IKK␥), which mediates upstream signals into activation of Article, publication date, and citation information can be found at

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“…All the 46 imidazothienopyrazine compounds and their bioactivity values were taken from the latest research report of Belema et al [7] ( Table I). The dataset is randomly separated into a training set of 36 compounds and a test set of 10 compounds.…”

Section: Datasetmentioning

confidence: 99%

“…Very recently, imidazothienopyrazine compounds were reported to possess good IKK-b inhibitory activities [7]. But a systematic quantitative structure-activity relationship (QSAR) study is absent for imidazothienopyrazines as IKK-b inhibitors.…”

Section: Introductionmentioning

confidence: 99%

QSAR studies on imidazothienopyrazines as IKK‐β inhibitors: from 2D to 3D

Long

Liu

et al. 2009

Journal of Chemometrics

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This paper presents the investigation of quantitative structure-activity relationship (QSAR) for imidazothienopyrazines from 2D to 3D, for assistance of developing new IKK-b inhibitors. In 2D-QSAR, we built linear and nonlinear models by heuristic method (HM) and Support Vector Machine (SVM) methods, respectively. The resultsshowed that the nonlinear model is more precise to predict the activities of imidazothienopyrazines. In 3D-QSAR, Phase methodology was employed, resulting in a successful model for prediction of imidazothienopyrazines' bioactivities, and this model (R 2 (training set) ¼ 0.9717, R 2 (test set) ¼ 0.9209) is better than any one of 2D-QSAR models, linear or nonlinear. In addition, the discussion of 2D descriptors from 2D-QSAR and the 3D plots from Phase results provided suggestions and guidance to develop new compounds which may present better bioactivities against IKK-b.

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Synthesis and structure–activity relationship of imidazo(1,2-a)thieno(3,2-e)pyrazines as IKK-β inhibitors

Cited by 36 publications

References 16 publications

Chemical biology of inflammatory cytokine signaling

Chemical biology of inflammatory cytokine signaling

Periodic, Partial Inhibition of IκB Kinase β-Mediated Signaling Yields Therapeutic Benefit in Preclinical Models of Rheumatoid Arthritis

QSAR studies on imidazothienopyrazines as IKK‐β inhibitors: from 2D to 3D

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