更新于：2024-11-01

PDE4 x PDE7A

更新于：2024-11-01

基本信息

关联

项与 PDE4 x PDE7A 相关的药物

YM-393059

靶点

PDE4 x PDE7A

作用机制

PDE4抑制剂 [+1]

在研机构

Astellas Pharma, Inc.

原研机构

Astellas Pharma, Inc.

在研适应症

自身免疫性疾病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PDE4 x PDE7A 相关的临床结果

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100 项与 PDE4 x PDE7A 相关的转化医学

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0 项与 PDE4 x PDE7A 相关的专利（医药）

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项与 PDE4 x PDE7A 相关的文献（医药）

2023-08-01·Cellular signalling

Phosphodiesterase 7 as a therapeutic target - Where are we now?

Review

作者: Zorn, Alina ; Baillie, George

Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyse the intracellular second messengers cAMP and cGMP to their inactive forms 5'AMP and 5'GMP. Some members of the PDE family display specificity towards a single cyclic nucleotide messenger, and PDE4, PDE7, and PDE8 specifically hydrolyse cAMP. While the role of PDE4 and its use as a therapeutic target have been well studied, less is known about PDE7 and PDE8. This review aims to collate the present knowledge on human PDE7 and outline its potential use as a therapeutic target. Human PDE7 exists as two isoforms PDE7A and PDE7B that display different expression patterns but are predominantly found in the central nervous system, immune cells, and lymphoid tissue. As a result, PDE7 is thought to play a role in T cell activation and proliferation, inflammation, and regulate several physiological processes in the central nervous system, such as neurogenesis, synaptogenesis, and long-term memory formation. Increased expression and activity of PDE7 has been detected in several disease states, including neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's disease, autoimmune diseases such as multiple sclerosis and COPD, and several types of cancer. Early studies have shown that administration of PDE7 inhibitors may ameliorate the clinical state of these diseases. Targeting PDE7 may therefore provide a novel therapeutic strategy for targeting a broad range of disease and possibly provide a complementary alternative to inhibitors of other cAMP-selective PDEs, such as PDE4, which are severely limited by their side-effects.

2023-01-01·Progress in Neuro-Psychopharmacology and Biological Psychiatry

Neuronal lack of PDE7a disrupted working memory, spatial learning, and memory but facilitated cued fear memory in mice

Article

作者: Garcia, Ana ; Liu, Zizhen ; Lipina, Tatiana V ; Martinez, Ana ; Li, Shupeng ; He, Kaiwu ; Ali, Tahir ; Gil, Carmen ; Li, Axiang ; Qiang, Hao ; Liufang, He ; Gao, Ruyan ; Li, Ningning ; Li, Tao

BACKGROUNDPDEs regulate cAMP levels which is critical for PKA activity-dependent activation of CREB-mediated transcription in learning and memory. Inhibitors of PDEs like PDE4 and Pde7 improve learning and memory in rodents. However, the role of PDE7 in cognition or learning and memory has not been reported yet.METHODSTherefore, we aimed to explore the cognitive effects of a PDE7 subtype, PDE7a, using combined pharmacological and genetic approaches.RESULTSPDE7a-nko mice showed deficient working memory, impaired novel object recognition, deficient spatial learning & memory, and contextual fear memory, contrary to enhanced cued fear memory, highlighting the potential opposite role of PDE7a in the hippocampal neurons. Further, pharmacological inhibition of PDE7 by AGF2.20 selectively strengthens cued fear memory in C57BL/6 J mice, decreasing its extinction but did not affect cognitive processes assessed in other behavioral tests. The further biochemical analysis detected deficient cAMP in neural cell culture with genetic excision of the PDE7a gene, as well as in the hippocampus of PDE7a-nko mice in vivo. Importantly, we found overexpression of PKA-R and the reduced level of pPKA-C in the hippocampus of PDE7a-nko mice, suggesting a novel mechanism of the cAMP regulation by PDE7a. Consequently, the decreased phosphorylation of CREB, CAMKII, eif2a, ERK, and AMPK, and reduced total level of NR2A have been found in the brain of PDE7a-nko animals. Notably, genetic excision of PDE7a in neurons was not able to change the expression of NR2B, BDNF, synapsin1, synaptophysin, or snap25.CONCLUSIONAltogether, our current findings demonstrated, for the first time, the role of PDE7a in cognitive processes. Future studies will untangle PDE7a-dependent neurobiological and molecular-cellular mechanisms related to cAMP-associated disorders.

2021-09-01·Archiv der Pharmazie4区 · 医学

Design, synthesis, and pharmacological characterization of some 2‐substituted‐3‐phenyl‐quinazolin‐4(3H)‐one derivatives as phosphodiesterase inhibitors

4区 · 医学

Article

作者: Amin, Kamilia M. ; Ibrahim, Nahla R. ; George, Riham F. ; Mohamed, Nada M. ; Hegazy, Gehan H.

AbstractSome 3‐phenyl‐quinazolin‐4(3H)‐one‐2‐thioethers (3a–e, 5a,b, 7a–e, 9a–d, 10a–d, and 12) along with 2‐aminoquinazoline derivatives 13a–c were prepared and screened for their in vitro phosphodiesterase (PDE) inhibitory activity. Some compounds such as 7d,e, 9a,b,d, 10a,d, and 13b exhibited promising activity as compared with the non‐selective PDE inhibitor IBMX. This inhibitory activity was validated by molecular docking in the active site of PDE7A and PDE4 to investigate their selectivity. Furthermore, the most active compound 10d (IC50 = 1.15 μM) was tested in vivo using behavioral tests. Compound 10d was able to pass the blood–brain barrier and improve scopolamine‐induced cognitive deficits. Therefore, this core can be considered as a promising scaffold for further optimization to obtain new compounds with better PDE7A selective inhibition.