The discovery of N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases

Brown, David; Cumming, John G.; Bethel, Paul A.; Finlayson, Jonathan; Gerhardt, S.; Nash, Ian A.; Pauptit, Richard A.; Pike, Kurt G.; Reid, A. C.; Snelson, Wendy L.; Swallow, Steve; Thompson, Caroline R.

doi:10.1016/j.bmcl.2012.04.116

Cited by 11 publications

(6 citation statements)

References 24 publications

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“…Studies have indicated that p38 MAPK plays an important role in regulating inflammatory response, [25][26][27] as it was an upstream regulator of a variety of inflammatory cytokines, such as TNF-a, IL-1, and IL-6, which in return control the inflammatory response inside and outside cells. 28 There is a variety of signal transduction pathways involved in the development of AP inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

PSD-95 protects the pancreas against pathological damage through p38 MAPK signaling pathway in acute pancreatitis

Guo

Wang

et al. 2021

Exp Biol Med (Maywood)

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Acute pancreatitis is one of the leading causes of gastrointestinal disorder-related hospitalizations, yet its pathogenesis remains to be fully elucidated. Postsynaptic density protein-95 (PSD-95) is closely associated with tissue inflammation and injury. We aimed to investigate the expression of PSD-95 in pancreatic acinar cells, and its function in regulating the inflammatory response and pancreatic pathological damage in acute pancreatitis. A mouse model of edematous acute pancreatitis was induced with caerulein and lipopolysaccharide in C57BL/6 mice. Tat-N-dimer was injected to inhibit the PSD-95 activity separately, or simultaneously with SB203580, inhibitor of p38 MAPK phosphorylation. Rat pancreatic acinar cells AR42J were cultured with 1 μM caerulein to build a cell model of acute pancreatitis. PSD-95-knockdown and negative control cell lines were constructed by lentiviral transfection of AR42J cells. Paraffin-embedded pancreatic tissue samples were processed for routine HE staining to evaluate the pathological changes of human and mouse pancreatic tissues. Serum amylase and inflammatory cytokine levels were detected with specific ELISA kits. Immunofluorescence, immunohistochemical, Western-blot, and qRT-PCR were used to detect the expression levels of PSD-95, p38, and phosphorylated p38. Our findings showed that PSD-95 is expressed in the pancreatic tissues of humans, C57BL/6 mice, and AR42J cells, primarily in the cytoplasm. PSD-95 expression increased at 2 h, reaching the peak at 6 h in mice and 12 h in AR42J cells. IL-6, IL-8, and TNF-α increased within 2 h of disease induction. The pancreatic histopathologic score was greater in the PSD-95 inhibition group compared with the control ( P < 0.05), while it was lesser when phosphorylation of p38 MAPK was inhibited compared with the PSD-95 inhibition group ( P < 0.05). Moreover, phosphorylation of p38 MAPK increased statistically after PSD-95 knocked-down. In conclusion, PSD-95 effectively influences the pathological damage of the pancreas in acute pancreatitis by affecting the phosphorylation of p38 MAPK.

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Section: Discussionmentioning

confidence: 99%

PSD-95 protects the pancreas against pathological damage through p38 MAPK signaling pathway in acute pancreatitis

Guo

Wang

et al. 2021

Exp Biol Med (Maywood)

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“…The earliest compound 67 had related inhibitory activities, but its water solubility was poor and plasma protein binding was quite high. Previous studies have shown that its terminal heteraryl methoxy can be removed without significantly reducing potency and replaced by side chains/rings containing alkaline amines, thereby improving solubility and plasma protein binding 167 . D.S.…”

Section: P38mapk Small Molecule Inhibitorsmentioning

confidence: 99%

p38 mitogen‐activated protein kinase: Functions and targeted therapy in diseases

Zheng,

Li,

Wang

et al. 2023

MedComm – Oncology

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P38 mitogen‐activated protein kinase (p38MAPK) is a multifunctional protein kinase that plays an important role in human normal physiological activities and a variety of major diseases, and its signaling pathway affects a variety of regulatory factors in vivo, which is related to cell cycle, survival, metabolism, and differentiation. The four subtypes of p38MAPK have significant differences in their distribution, content, and effects in the body. The inhibitors of the four subtypes play potential roles in regulating cancer, neurodegenerative diseases, inflammation, and cardiovascular diseases, making it an attractive target for drug development. So far, an increasing number of p38MAPK inhibitors have been developed for targeted therapy in diseases, among which some representative compounds have entered clinical trials. Therefore, this review aims to provide a summary of the structural characteristics, signaling pathways of P38MAPK and the relationship between p38MAPK and disease, along with an overview of the binding modes and structure–activity relationships of small molecule inhibitors targeting four p38MAPK subtypes, and summarizes the challenges about the development of p38MAPK inhibitors, hoping to provide a valuable reference for the development and application of novel inhibitors.

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“…Its efficacy is associated with the inhibition of such transcription factors as NF-κB and NFATc1 as well as multiple protein kinases, including p38, ERK and JNK [ 14 ]. AZD6703 is a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases [ 16 ]. PF-4950834 blocks stromal cell-derived factor-1α-mediated chemotaxis of T lymphocytes in vitro and the synthesis of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in activated human endothelial cells in vitro [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammation of N-Benzyl-4-Bromobenzamide in Lipopolysaccharide-Induced Human Gingival Fibroblasts

2015

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Objective: To evaluate the effect of N-benzyl-4-bromobenzamide (NBBA) on lipopolysaccharide (LPS)-induced IL-6 and prostaglandin E₂ (PGE₂) production in human gingival fibroblasts (HGFs). Material and Methods: The benzamide compound was synthesized. The condition for IL-6 production of HGFs after induction with LPS was optimized. The HGFs were incubated with NBBA (10 µg/ml) for 30 min before LPS (1 μg/ml) was added. After 24 h of incubation time, the culture media were harvested and their IL-6 and PGE₂ contents were determined using an enzyme-linked immunosorbent assay. Prednisolone (PDS) and NS-398 were used as positive controls. Statistical analysis of the IL-6 and PGE₂ contents was performed using the ANOVA test followed by the Tukey multiple-comparisons test to compare replicate means. p < 0.001 was considered statistically significant. Results: The maximum IL-6 production was achieved when HGFs were exposed to 1 μg/ml of LPS for 24 h, which was inhibited by the IL-6 immunosuppressant PDS. The benzamide compound, NBBA, exhibited a potent anti-IL-6 activity with inhibition of 35.6 ± 0.5%, significantly different from in the LPS-induced HGFs (p < 0.001). In addition, it inhibited 75.6 ± 0.52% PGE₂ production. Cell viability was not significantly affected by treatment with NBBA at a concentration <10 µg/ml (p < 0.001). Conclusions: NBBA exhibited an inhibitory effect on the production of IL-6 and PGE₂ in LPS-induced HGFs. It could serve as a compound with inhibiting inflammatory activity in periodontal disease.

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The discovery of N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases

Cited by 11 publications

References 24 publications

PSD-95 protects the pancreas against pathological damage through p38 MAPK signaling pathway in acute pancreatitis

PSD-95 protects the pancreas against pathological damage through p38 MAPK signaling pathway in acute pancreatitis

p38 mitogen‐activated protein kinase: Functions and targeted therapy in diseases

Anti-Inflammation of N-Benzyl-4-Bromobenzamide in Lipopolysaccharide-Induced Human Gingival Fibroblasts

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