Antihypertensive activity of a new c-Jun N-terminal kinase inhibitor in spontaneously hypertensive rats

Плотников, М. Б.; Алиев, О. И.; Shamanaev, Aleksandr; Сидехменова, А. В.; Анищенко, А. М.; Фомина, Т. И.; Рыдченко, В. С.; Khlebnikov, Аndrei I.; Anfinogenova, Yana; Schepetkin, Igor A.; Atochin, Dmitriy N.

doi:10.1038/s41440-020-0446-9

Cited by 11 publications

(9 citation statements)

References 56 publications

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“…Preclinical pharmacokinetic studies in rats demonstrated that after i.p. administration of IQ-1S, a rapid rise in the serum concentration was observed, peaking at 5 min, and the half-life in circulation was 12 h (Plotnikov et al, 2020). When mice were dosed with 30 mg/kg IQ-1S i.p., the serum exposure of the compound was also good, with AUC 0-12 h values of 7.4 µM/h (Schepetkin et al, 2012).…”

Section: Tryp and Tryp-ox Reduce Cia Severitymentioning

confidence: 99%

Therapeutic Effects of Tryptanthrin and Tryptanthrin-6-Oxime in Models of Rheumatoid Arthritis

et al. 2020

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Rheumatoid arthritis (RA) is a chronic autoimmune disease involving joint and bone damage that is mediated in part by proteases and cytokines produced by synovial macrophages and fibroblast-like synoviocytes (FLS). Although current biological therapeutic strategies for RA have been effective in many cases, new classes of therapeutics are needed. We investigated anti-inflammatory properties of the natural alkaloid tryptanthrin (TRYP) and its synthetic derivative tryptanthrin-6-oxime (TRYP-Ox). Both TRYP and TRYP-Ox inhibited matrix metalloproteinase (MMP)-3 gene expression in interleukin (IL)-1b-stimulated primary human FLS, as well as IL-1b-induced secretion of MMP-1/3 by FLS and synovial SW982 cells and IL-6 by FLS, SW982 cells, human umbilical vein endothelial cells (HUVECs), and monocytic THP-1 cells, although TRYP-Ox was generally more effective and had no cytotoxicity in vitro. Evaluation of the therapeutic potential of TRYP and TRYP-Ox in vivo in murine arthritis models showed that both compounds significantly attenuated the development of collagen-induced arthritis (CIA) and collagen-antibody-induced arthritis (CAIA), with comparable efficacy. Collagen II (CII)specific antibody levels were similarly reduced in TRYP-and TRYP-Ox-treated CIA mice. TRYP and TRYP-Ox also suppressed proinflammatory cytokine production by lymph node cells from CIA mice, with TRYP-Ox being more effective in inhibiting IL-17A, granulocyte-macrophage colony-stimulating factor (GM-CSF), and receptor activator of nuclear factor-kB ligand (RANKL). Thus, even though TRYP-Ox generally had a better in vitro profile, possibly due to its ability to inhibit c-Jun N-terminal kinase (JNK), both TRYP and TRYP-Ox were equally effective in inhibiting the clinical symptoms and damage associated with RA. Overall, TRYP and/or TRYP-Ox may represent potential new directions for the pursuit of novel treatments for RA.

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Section: Tryp and Tryp-ox Reduce Cia Severitymentioning

confidence: 99%

Therapeutic Effects of Tryptanthrin and Tryptanthrin-6-Oxime in Models of Rheumatoid Arthritis

et al. 2020

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“…After global ischemia/reperfusion, 30 decreased the number of animals with severe neurological deficit, increased density of the pyramidal neurons in the hippocampal CA1 area, improved the cerebral microcirculation, and attenuated the endothelial dysfunction. In addition, compound 30 treatment resulted in decreased systolic blood pressure, mean arterial blood pressure, and total peripheral resistance in spontaneously hypertensive rats [ 114 ]. Overall, the antihypertensive effects of compound 30 may be due to a combination of the inhibition of myocardial and aorta remodeling, attenuation of blood viscosity due to hematocrit decrease, vasodilatory effects, and decreased endothelin-1 production by the endothelial cells.…”

Section: Miscellaneous Oxime Group-containing Kinase Inhibitorsmentioning

confidence: 99%

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

et al. 2021

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Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are kinase inhibitors and have been shown to inhibit over 40 different kinases, including AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K), cyclin-dependent kinase (CDK), serine/threonine kinases glycogen synthase kinase 3 α/β (GSK-3α/β), Aurora A, B-Raf, Chk1, death-associated protein-kinase-related 2 (DRAK2), phosphorylase kinase (PhK), serum and glucocorticoid-regulated kinase (SGK), Janus tyrosine kinase (JAK), and multiple receptor and non-receptor tyrosine kinases. Some oximes are inhibitors of lipoxygenase 5, human neutrophil elastase, and proteinase 3. The oxime group contains two H-bond acceptors (nitrogen and oxygen atoms) and one H-bond donor (OH group), versus only one H-bond acceptor present in carbonyl groups. This feature, together with the high polarity of oxime groups, may lead to a significantly different mode of interaction with receptor binding sites compared to corresponding carbonyl compounds, despite small changes in the total size and shape of the compound. In addition, oximes can generate nitric oxide. This review is focused on oximes as kinase inhibitors with anticancer and anti-inflammatory activities. Oximes with non-kinase targets or mechanisms of anti-inflammatory activity are also discussed.

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“…NMR spectra were recorded on Bruker spectrometers (600 MHz for 1 H, 150 MHz for 13 C, and 280 MHz for 19 F NMR). 1 H, 13 C, and 19 F NMR spectra for the most potent compounds 4a, 4b, 4e, 4f, and 4m are shown in Supplementary Materials.…”

Section: Chemistrymentioning

confidence: 99%

“…JNK1 and JNK2 are found in all cells and tissues of the body, whereas JNK3 is expressed mainly in the brain, heart, and testicles [ 2 ]. Previous studies show that JNKs play an important role in the regulation of signaling pathways involved in inflammation, apoptosis, and necrosis [ 6 , 7 , 8 , 9 ] and in a wide range of diseases, including multiple sclerosis, rheumatoid arthritis, osteoarthritis, insulin resistance, inflammatory bowel diseases, cancer, stroke, renal ischemia, essential hypertension, Alzheimer’s disease, and Parkinson’s disease [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the therapeutic efficacy of lead compounds should be evaluated in appropriate ischemia/reperfusion models. rheumatoid arthritis, osteoarthritis, insulin resistance, inflammatory bowel diseases, cancer, stroke, renal ischemia, essential hypertension, Alzheimer's disease, and Parkinson's disease [10][11][12][13][14][15][16][17][18][19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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Novel c-Jun N-Terminal Kinase (JNK) Inhibitors with an 11H-Indeno[1,2-b]quinoxalin-11-one Scaffold

et al. 2021

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c-Jun N-terminal kinase (JNK) plays a central role in stress signaling pathways implicated in important pathological processes, including rheumatoid arthritis and ischemia-reperfusion injury. Therefore, inhibition of JNK is of interest for molecular targeted therapy to treat various diseases. We synthesized 13 derivatives of our reported JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime and evaluated their binding to the three JNK isoforms and their biological effects. Eight compounds exhibited submicromolar binding affinity for at least one JNK isoform. Most of these compounds also inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation and interleukin-6 (IL-6) production in human monocytic THP1-Blue cells and human MonoMac-6 cells, respectively. Selected compounds (4f and 4m) also inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. We conclude that indenoquinoxaline-based oximes can serve as specific small-molecule modulators for mechanistic studies of JNKs, as well as potential leads for the development of anti-inflammatory drugs.

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Antihypertensive activity of a new c-Jun N-terminal kinase inhibitor in spontaneously hypertensive rats

Cited by 11 publications

References 56 publications

Therapeutic Effects of Tryptanthrin and Tryptanthrin-6-Oxime in Models of Rheumatoid Arthritis

Therapeutic Effects of Tryptanthrin and Tryptanthrin-6-Oxime in Models of Rheumatoid Arthritis

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

Novel c-Jun N-Terminal Kinase (JNK) Inhibitors with an 11H-Indeno[1,2-b]quinoxalin-11-one Scaffold

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