5-LOX inhibitors(Arachidonate 5-lipoxygenase inhibitors), COX inhibitors(Cyclooxygenases inhibitors), p38α inhibitors(P38 α mitogen-activated protein kinase inhibitors)

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic Disease

Active Indication

Lewy Body DiseaseParkinson Disease

Inactive Indication

Rheumatoid Arthritis

Originator Organization

GSK Plc

Active Organization

National Institutes of Health

Inactive Organization

GSK Plc

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC16H12FN3S

InChIKeyYOELZIQOLWZLQC-UHFFFAOYSA-N

CAS Registry72873-74-6

100 Clinical Results associated with SKF-86002

100 Translational Medicine associated with SKF-86002

100 Patents (Medical) associated with SKF-86002

Literatures (Medical) associated with SKF-86002

01 Dec 2024·Journal of Stroke and Cerebrovascular Diseases

Blockage of p38MAPK in astrocytes alleviates brain damage in a mouse model of embolic stroke through the CX43/AQP4 axis

Article

Author: Wu, Zhiping ; Tu, Jianglong ; Zhang, Yangbo ; Liu, Xu ; Yin, Min ; Chen, Weiping ; Qin, Yiren

BACKGROUNDCerebral edema, a significant complication arising from acute ischemic stroke (IS), has a critical influence on morbidity and mortality. p38MAPK has been shown to promote neuronal apoptosis and brain damage. However, the role of the p38MAPK inhibitor SKF-86002 in protecting against ischemic injury and cerebral edema remains unclear.METHODSInfarct area was examined by TTC staining in middle cerebral artery occlusion (MCAO) mice. Neurological score and brain water content were evaluated. TUNEL and NeuN staining were used to assess neuronal apoptosis and the survival of neurons. Blood-brain barrier (BBB) permeability was determined by Evans blue. Double immunofluorescence staining detected the colocalization of AQP4 and CX43 in astrocytes. IHC staining revealed CX43 and AQP4 expression. EDU staining detected the proliferation of Oxygen and glucose deprivation/reoxygenation (OGD/R)-treated astrocytes. Levels of oxidative stress markers were determined using commercial kits. ELISA was used to assess the secretion of pro-inflammatory factors. RT-qPCR measured the expression of CX43, AQP4 and pro-inflammatory factors. Western blot analyzed the levels of p-p38/p38, AQP4 and CX43. Co-immunoprecipitation (Co-IP) determined the interaction between CX43 and AQP4.RESULTSSKF-86002 attenuated brain damage, edema, and neuronal apoptosis in MCAO mice. Astrocyte proliferation was suppressed, and oxidative stress and inflammation were alleviated by SKF-86002 treatment. SKF-86002 negatively regulated p38 signaling and the expression of AQP4 and CX43. Additionally, the expression of CX43/AQP4 within astrocytes was modulated by SKF-86002.CONCLUSIONIn summary, SKF-86002 alleviated IS injury and cerebral edema by inhibiting astrocyte proliferation, oxidative stress and inflammation. This effect was associated with the suppression of CX43/AQP4, suggesting that SKF-86002 shows promise as a novel therapeutic approach for preventing IS.

01 May 2024·Microbes and Infection

Prevotella, a dominant bacterium in young people with stage Ⅲ periodontitis, related to the arachidonic acid metabolism pathway

Article

Author: Guo, Yue ; Zhao, Jie ; Ouyang, Zeyue ; Su, Xiaolin ; Hu, Jing ; Zhao, Yaqiong ; Chen, Ningxin ; Feng, Yao ; Tan, Li ; Chen, Yun ; Feng, Yunzhi ; Ye, Qin

OBJECTSAs periodontitis progresses, the oral microbiome changes dynamically. The aim of this study is to evaluate the dominant bacteria of adults with stage III periodontitis and investigate potential pathways related to the dominant bacteria.MATERIALS AND METHODS16S rRNA sequencing was carried out to detect the differences in the oral microbiome between adult with stage Ⅰ and stage Ⅲ periodontitis and find the dominant bacteria in each group. The inhibitor of the predominant pathway for stage Ⅲ periodontitis was used to investigate the role of the dominant bacteria in periodontitis in vivo and in vitro.RESULTSThere was no significant difference in the α-diversity between the two groups. The results of β-diversity showed that the samples were divided into different groups according to the stage of periodontitis. The dominant bacteria in youths with stage Ⅲ periodontitis was Prevotella and may be related to the arachidonic acid metabolism pathway. Administration of SKF-86002 suppressed the expression of inflammation mediators in vivo and vitro.CONCLUSIONSPrevotella was the one dominant bacteria in young people with stage Ⅲ periodontitis and was related to the arachidonic acid metabolism pathway.

10 May 2023·Science Translational MedicineQ1 · MEDICINE

Inhibition of p38α MAPK restores neuronal p38γ MAPK and ameliorates synaptic degeneration in a mouse model of DLB/PD

Q1 · MEDICINE

Article

Author: Cookson, Mark R ; Figg, William D ; Lee, Seung-Jae ; Peer, Cody J ; Horan-Portelance, Liam ; Reed, Xylena ; Kim, Changyoun ; Szabo, Marcell ; Masliah, Eliezer ; Iba, Michiyo ; Ding, Jinhui ; Kwon, Somin ; Wrasidlo, Wolf ; Overk, Cassia ; Rissman, Robert A

Alterations in the p38 mitogen-activated protein kinases (MAPKs) play an important role in the pathogenesis of dementia with Lewy bodies (DLB) and Parkinson’s disease (PD). Activation of the p38α MAPK isoform and mislocalization of the p38γ MAPK isoform are associated with neuroinflammation and synaptic degeneration in DLB and PD. Therefore, we hypothesized that p38α might be associated with neuronal p38γ distribution and synaptic dysfunction in these diseases. To test this hypothesis, we treated in vitro cellular and in vivo mouse models of DLB/PD with SKF-86002, a compound that attenuates inflammation by inhibiting p38α/β, and then investigated the effects of this compound on p38γ and neurodegenerative pathology. We found that inhibition of p38α reduced neuroinflammation and ameliorated synaptic, neurodegenerative, and motor behavioral deficits in transgenic mice overexpressing human α-synuclein. Moreover, treatment with SKF-86002 promoted the redistribution of p38γ to synapses and reduced the accumulation of α-synuclein in mice overexpressing human α-synuclein. Supporting the potential value of targeting p38 in DLB/PD, we found that SKF-86002 promoted the redistribution of p38γ in neurons differentiated from iPS cells derived from patients with familial PD (carrying the A53T α-synuclein mutation) and healthy controls. Treatment with SKF-86002 ameliorated α-synuclein–induced neurodegeneration in these neurons only when microglia were pretreated with this compound. However, direct treatment of neurons with SKF-86002 did not affect α-synuclein–induced neurotoxicity, suggesting that SKF-86002 treatment inhibits α-synuclein–induced neurotoxicity mediated by microglia. These findings provide a mechanistic connection between p38α and p38γ as well as a rationale for targeting this pathway in DLB/PD.

100 Deals associated with SKF-86002

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Lewy Body Disease	Preclinical	US	National Institutes of Health	10 May 2023
Parkinson Disease	Preclinical	US	National Institutes of Health	10 May 2023
Rheumatoid Arthritis	Preclinical	-	GSK Plc	-

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