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更新于：2025-05-07

p38 MAPK x PDE4

更新于：2025-05-07

基本信息

关联

项与 p38 MAPK x PDE4 相关的药物

CBS-3595

靶点

PDE4 x p38 MAPK

作用机制

PDE4抑制剂 [+1]

在研机构

c-a-i-r biosciences GmbH [+1]

原研机构

Merckle GmbH

在研适应症

类风湿关节炎

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

CGH-2466

靶点

A1R x PDE4 x p38 MAPK

作用机制

A1R拮抗剂 [+2]

在研机构-

原研机构

Novartis AG

在研适应症-

非在研适应症

哮喘 [+1]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 p38 MAPK x PDE4 相关的临床结果

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100 项与 p38 MAPK x PDE4 相关的转化医学

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0 项与 p38 MAPK x PDE4 相关的专利（医药）

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项与 p38 MAPK x PDE4 相关的文献（医药）

2025-02-13·Journal of Medicinal Chemistry

Design, Synthesis, and Evaluation of Selective PDE4 Inhibitors for the Therapy of Pulmonary Injury

Article

作者: Song, Liyan ; Li, Gang ; Bai, Dan ; Li, Mengjie ; Ke, Hengming ; Guan, Wen ; Yao, Hongliang ; Ou, Yanghui ; Liu, Yuanhui ; Ye, Lianbao ; Huang, Peiming ; Li, Jiayu ; Zeng, Zhijun ; Tang, Haiyang ; Zhang, Guoping

Pulmonary inflammation is the main cause of lung injury. Phosphodiesterase 4 (PDE4) is a promising anti-inflammatory target for the treatment of respiratory diseases. Herein, we designed and synthesized 43 compounds in two novel series of benzimidazole derivatives as PDE4 inhibitors. Among them, compound A5 showed highly selective inhibition of PDE4, good safety, and liver microsomal stability in vitro. A5 administration remarkably attenuated inflammatory infiltration and pathologic injury of the lung in models of acute lung injury in mice and chronic obstructive pulmonary disease (COPD) in mice. In addition, A5 enhanced sputum secretion, relieved cough in mice, and inhibited phosphorylation of p38 MAP kinase, an important protein in the regulation of lung injury. Overall, A5, as an effective PDE4 inhibitor without acute toxicity and gastrointestinal reaction, may be a potent candidate for the treatment of pulmonary injury.

2022-02-01·Toxicology and Applied Pharmacology3区 · 医学

Roflupram attenuates α-synuclein-induced cytotoxicity and promotes the mitochondrial translocation of Parkin in SH-SY5Y cells overexpressing A53T mutant α-synuclein

3区 · 医学

Article

作者: Wang, Haitao ; Qiu, Shuqing ; Zhong, Jiahong ; Dong, Wenli ; Li, Mengfan ; Xu, Jiangping ; Li, Xing ; Qin, Yunyun

We have previously shown that inhibition of cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) protects against cellular toxicity in neuronal cells. Since α-synuclein (α-syn) toxicity contributes to the neurodegeneration of Parkinson's disease (PD). The aim of this study was to explore the effects and mechanisms of PDE4 on α-syn-induced neuronal toxicity. Using mutant human A53T α-syn overexpressed SH-SY5Y cells, we found that PDE4B knockdown reduced cellular apoptosis. Roflupram (ROF, 20 μM), a selective PDE4 inhibitor, produced similar protective effects and restored the morphological alterations of mitochondria. Mechanistic studies identified that α-syn enhanced the phosphorylation of Parkin at Ser131, followed by the decreased mitochondrial translocation of Parkin. Whereas both PDE4B knockdown and PDE4 inhibition by ROF blocked the effects of α-syn on Parkin phosphorylation and mitochondrial translocation. Moreover, PDE4 inhibition reversed the increase in the phosphorylation of p38 mitogen-activated protein kinase (MAPK) induced by α-syn. ROF treatment also reduced the binding of p38 MAPK to Parkin. Consistently, overexpression of PDE4B blocked the roles of ROF on p38 MAPK phosphorylation, Parkin phosphorylation, and the subsequent mitochondrial translocation of parkin. Furthermore, PDE4B overexpression attenuated the protective role of ROF, as evidenced by reduced mitochondria membrane potential and increased cellular apoptosis. Interestingly, ROF failed to suppress α-syn-induced cytotoxicity in the presence of a protein kinase A (PKA) inhibitor H-89. Our findings indicate that PDE4 facilitates α-syn-induced cytotoxicity via the PKA/p38 MAPK/Parkin pathway in SH-SY5Y cells overexpressing A53T mutant α-synuclein. PDE4 inhibition by ROF is a promising strategy for the prevention and treatment of α-syn-induced neurodegeneration.

2022-02-01·Journal of the European Academy of Dermatology and Venereology2区 · 医学

Apremilast effectively inhibits TNFα‐induced vascular inflammation in human endothelial cells

2区 · 医学

Article

作者: Doll, M. ; Grasmik, T. ; Jakob, T. ; Otto, M. ; Dorn, B. ; Meissner, M. ; Hrgovic, I.

AbstractBackgroundPatients with chronic inflammatory diseases (e.g. psoriasis and rheumatoid arthritis) are at increased risk for the development of atherosclerosis and cardiovascular diseases (CVD). Previous studies have suggested that phosphodiesterase 4 (PDE4) inhibitors possess anti‐inflammatory properties.ObjectivesHere we examined the effect of the PDE4 inhibitor apremilast, a well‐established anti‐psoriatic drug, on pro‐inflammatory responses in TNFα‐activated endothelial cells.MethodsHuman umbilical vein endothelial cells (HUVEC) were treated with tumour necrosis factor‐α (TNFα) in the presence or absence of apremilast. Expression levels of pro‐inflammatory cytokines, chemokines and adhesion molecules were assessed by ELISA, western blot and RT‐PCR. Effects of apremilast on adhesion and transendothelial migration (TEM) of THP‐1 monocytic cells were analysed in transwell assays.ResultsApremilast suppressed TNFα‐induced expression and secretion of important endothelial and monocytic pro‐inflammatory factors, including granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), C‐X‐C motif chemokine ligand 10 (CXCL10), chemokine (C‐C motif) ligand 2 (CCL2), vascular cell adhesion molecule 1 (VCAM‐1), E‐selectin and matrix metalloproteinase‐9 (MMP9). Functionally, apremilast reduced adhesion of THP‐1 cells to activated HUVECs and TEM in response to TNFα. Mechanistically, apremilast suppressed activation of nuclear factor κB (NFκB) and mitogen‐activated protein kinases (MAPK) signalling in activated HUVECs. Furthermore, inhibition of p38, C‐Jun‐N‐terminale Kinase (JNK) and NFκB in activated HUVECs decreased expression of GM‐CSF, VCAM‐1 and E‐selectin. Additionally, apremilast decreased IL‐17A‐induced secretion of IL‐6 and CCL2.ConclusionsWe demonstrate that apremilast has distinct anti‐inflammatory effects in activated HUVECs, indicating that apremilast could have the therapeutic potential to prevent higher risk for CVD in patients with chronic inflammatory diseases.

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