Discovery and optimization of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1

Hornberger, Keith R.; Berger, Dan M.; Crew, Andrew P.; Dong, Hanqing; Kleinberg, Andrew; Li, Anhu; Medeiros, Matthew R.; Mulvihill, Mark J.; Siu, Kam; Tarrant, James; Wang, Jing; Weng, Felix; Wilde, Victoria L.; Albertella, Mark R.; Bittner, Mark; Cooke, Andrew; Gray, Michael J.; Maresca, Paul; May, Earl W.; Meyn, Peter; Peick, William; Romashko, Darlene; Tanowitz, Michael; Tokar, Brianna

doi:10.1016/j.bmcl.2013.06.053

Cited by 20 publications

(10 citation statements)

References 14 publications

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“…Synthesis of 4,2,3]thiadiazole Despite the fact that 4,7-dibromobenzo[c][1,2,5]thiadiazole has been extensively studied for the past 20 years [1-8], its closest isomer, 4,7-dibromobenzo[d][1,2,3]thiadiazole 1, was first synthesized relatively recently in 2016 [9]. The obtaining of dibromide 1, as previously described [9], involves the bromination reaction of benzo [d][1,2,3]thiadiazole 2, which was obtained using the commercially available 2-aminobenzenethiol with a nitrosation reaction followed by intramolecular cyclization (Scheme 1) [19].…”

Section: Resultsmentioning

confidence: 99%

Benzothiadiazole vs. iso-Benzothiadiazole: Synthesis, Electrochemical and Optical Properties of D–A–D Conjugated Molecules Based on Them

et al. 2021

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This paper presents an improved synthesis of 4,7-dibromobenzo[d][1,2,3]thiadiazole from commercially available reagents. According to quantum-mechanical calculations, benzo[d][1,2,3]thiadiazole (isoВТD) has higher values of ELUMO and energy band gap (Eg), which indicates high electron conductivity, occurring due to the high stability of the molecule in the excited state. We studied the cross-coupling reactions of this dibromide and found that the highest yields of π-spacer–acceptor–π-spacer type compounds were obtained by means of the Stille reaction. Therefore, 6 new structures of this type have been synthesized. A detailed study of the optical and electrochemical properties of the obtained π-spacer–acceptor–π-spacer type compounds in comparison with isomeric structures based on benzo[c][1,2,5]thiadiazole (BTD) showed a red shift of absorption maxima with lower absorptive and luminescent capacity. However, the addition of the 2,2′-bithiophene fragment as a π-spacer resulted in an unexpected increase of the extinction coefficient in the UV/vis spectra along with a blue shift of both absorption maxima for the isoBTD-based compound as compared to the BTD-based compound. Thus, a thorough selection of components in the designing of appropriate compounds with benzo[d][1,2,3]thiadiazole as an internal acceptor can lead to promising photovoltaic materials.

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Section: Resultsmentioning

confidence: 99%

Benzothiadiazole vs. iso-Benzothiadiazole: Synthesis, Electrochemical and Optical Properties of D–A–D Conjugated Molecules Based on Them

et al. 2021

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“…To evaluate the reversible covalent properties of the described compounds, we reacted 13h with b-mercaptoethanol (BME) and 25 . Imidazopyridine core interacts with hinge region of TAK1 and pyridinyl nitrogen forms a hydrogen bond with D175.…”

Section: Resultsmentioning

confidence: 99%

“… Predicted binding mode of 13h with C174 of TAK1 kinase domain (PDB: 4L52) 25 . Imidazopyridine core interacts with hinge region of TAK1 and pyridinyl nitrogen forms a hydrogen bond with D175.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological activity of 2-cyanoacrylamide derivatives tethered to imidazopyridine as TAK1 inhibitors

Kang

Lee

Song

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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The importance of transforming growth factor beta-activated kinase 1 (TAK1) to cell survival has been demonstrated in many studies. TAK1 regulates signalling cascades, the NF-jB pathway and the mitogenactivated protein kinase (MAPK) pathway. TAK1 inhibitors can induce the apoptosis of cancerous cells, and irreversible inhibitors such as (5Z)-7-oxozeaenol are highly potent. However, they can react non-specifically with cysteine residues in proteins, which may have serious adverse effects. Reversible covalent inhibitors have been suggested as alternatives. We synthesised imidazopyridine derivatives as novel TAK1 inhibitors, which have 2-cyanoacrylamide moiety that can form reversible covalent bonding. A derivative with 2cyano-3-(6-methylpyridin-2-yl)acrylamide (13h) exhibited potent TAK1 inhibitory activity with an IC 50 of 27 nM. It showed a reversible reaction with b-mercaptoethanol, which supports its potential as a reversible covalent inhibitor.

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“… covalent [ 61 ] epoxyquinol 20000 n.a. covalent [ 62 ] AZ-TAK1 8 unpublished Type I [ 63 ] ABC-FP 28 4L53 Type I [ 64 , 65 ] PF-04358168 1640 2YIY Type II [ 66 ] PF-05381941 156 N/A Type II [ 66 ] NG-25 4 4O91 Type II [ 67 ] LYTAK1 N/A n.a. N/A [ 68 ] takinib 9.5 5V5N Type 1.5 [ 13 ] …”

Section: Tak1 As a Target For Inflammatory Disordersmentioning

confidence: 99%

TAK1: a potent tumour necrosis factor inhibitor for the treatment of inflammatory diseases

et al. 2020

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Aberrant tumour necrosis factor (TNF) signalling is a hallmark of many inflammatory diseases including rheumatoid arthritis (RA), irritable bowel disease and lupus. Maladaptive TNF signalling can lead to hyper active downstream nuclear factor (NF)-κβ signalling in turn amplifying a cell's inflammatory response and exacerbating disease. Within the TNF intracellular inflammatory signalling cascade, transforming growth factor-β-activated kinase 1 (TAK1) has been shown to play a critical role in mediating signal transduction and downstream NF-κβ activation. Owing to its role in TNF inflammatory signalling, TAK1 has become a potential therapeutic target for the treatment of inflammatory diseases such as RA. This review highlights the current development of targeting the TNF-TAK1 signalling axis as a novel therapeutic strategy for the treatment of inflammatory diseases.

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Discovery and optimization of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1

Cited by 20 publications

References 14 publications

Benzothiadiazole vs. iso-Benzothiadiazole: Synthesis, Electrochemical and Optical Properties of D–A–D Conjugated Molecules Based on Them

Benzothiadiazole vs. iso-Benzothiadiazole: Synthesis, Electrochemical and Optical Properties of D–A–D Conjugated Molecules Based on Them

Synthesis and biological activity of 2-cyanoacrylamide derivatives tethered to imidazopyridine as TAK1 inhibitors

TAK1: a potent tumour necrosis factor inhibitor for the treatment of inflammatory diseases

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