更新于：2024-09-05

PDE1A

更新于：2024-09-05

基本信息

别名

61 kDa Cam-PDE、Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A、Cam-PDE 1A

+ [5]

简介

Calcium/calmodulin-dependent cyclic nucleotide phosphodiesterase with a dual specificity for the second messengers cGMP and cAMP, which are key regulators of many important physiological processes. Has a higher efficiency with cGMP compared to cAMP.

关联

项与 PDE1A 相关的药物

PDE-1 inhibitors(Boehringer Ingelheim)

靶点

PDE1A

作用机制

PDE1A抑制剂

在研机构

Boehringer Ingelheim International GmbH

原研机构

Boehringer Ingelheim International GmbH

在研适应症

精神分裂症

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 PDE1A 相关的临床结果

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100 项与 PDE1A 相关的转化医学

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0 项与 PDE1A 相关的专利（医药）

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146

项与 PDE1A 相关的文献（医药）

2024-01-01·Frontiers in immunology

Gene expression meta-analysis reveals aging and cellular senescence signatures in scleroderma-associated interstitial lung disease.

Article

作者: Monica M Yang ; Seoyeon Lee ; Jessica Neely ; Monique Hinchcliff ; Paul J Wolters ; Marina Sirota

Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma-associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging- and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissues from 38 SSc-ILD and 18 healthy controls and found that markers (GDF15, COMP, and CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found that epithelial and fibroblast senescence signatures had a 3.6- and 3.7-fold enrichment, respectively, in the lung tissue of SSc-ILD and that lung aging genes (CDKN2A, FRZB, PDE1A, and NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in the lung tissue and found that, independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.

2023-12-19·Molecules (Basel, Switzerland)

Synthesis and Activity Evaluation of Vinpocetine-Derived Indole Alkaloids.

Article

作者: Zhang-Chao Dong ; Yang Shi ; Liang-Liang Zheng ; You-Ping Tian ; Jian Yang ; Ying Wei ; Ying Zhou ; Bo-Wen Pan

This study focuses on the synthesis of novel vinpocetine derivatives (2-25) and their biological evaluation. The chemical structures of the synthesized compounds were fully characterized using techniques such as ¹H NMR, ¹³C NMR, and HRMS. The inhibitory activity of the synthesized compounds on PDE1A was evaluated, and the results revealed that compounds 3, 4, 5, 12, 14, 21, and 25 exhibited superior inhibitory activity compared to vinpocetine. Compound 4, with a para-methylphenyl substitution, showed a 5-fold improvement in inhibitory activity with an IC₅₀ value of 3.53 ± 0.25 μM. Additionally, compound 25, with 3-chlorothiazole substitution, displayed an 8-fold increase in inhibitory activity compared to vinpocetine (IC₅₀ = 2.08 ± 0.16 μM). Molecular docking studies were conducted to understand the binding models of compounds 4 and 25 within the active site of PDE1A. The molecular docking study revealed additional binding interactions, such as π-π stacking and hydrogen bonding, contributing to the enhanced inhibitory activity and stability of the ligand-protein complexes. Overall, the synthesized vinpocetine derivatives demonstrated promising inhibitory activity on PDE1A, and the molecular docking studies provided insights into their binding modes, supporting further development of these compounds as potential candidates for drug research and development.

2023-12-01·Frontiers in bioscience (Landmark edition)

Metabolism-Related Prognostic Biomarkers, Purine Metabolism and Anti-Tumor Immunity in Colon Adenocarcinoma.

Article

作者: Hui Liu ; Yuexin Zhang ; Quanzheng Zhang ; Tongtong Zhang ; Tianqi Lu

BACKGROUND:

Metabolic reprogramming provides a new perspective for understanding cancer. The targeting of dysregulated metabolic pathways may help to reprogram the immune status of the tumor microenvironment (TME), thereby increasing the effectiveness of immune checkpoint therapy. Colorectal cancer (CRC), especially colon adenocarcinoma (COAD), is associated with poor patient survival. The aim of the present study was to identify novel pathways involved in the development and prognosis of COAD, and to explore whether these pathways could be used as targets to improve the efficacy of immunotherapy.

METHODS:

Metabolism-related differentially expressed genes (MRDEGs) between tumor and normal tissues were identified using The Cancer Genome Atlas (TCGA) dataset, together with metabolism-related prognostic genes (MRPGs). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed separately for the MRDEGs and MRPGs. Gene Set Variation Analysis (GSVA) was also performed to explore the role of purine metabolism in COAD tumorigenesis. Consensus clustering of purine metabolism genes with the overall survival (OS) of patients and with anti-tumor immunity was also performed. Pearson correlation analysis was used to identify potential targets that correlated strongly with the expression of immune checkpoints.

RESULTS:

A 6-gene signature that had independent prognostic significance for COAD was identified, together with a predictive model for risk stratification and prognosis. The most significantly enriched pathway amongst MRDEGs and MRPGs was purine metabolism. Differentially expressed purine metabolism genes could divide patients into two clusters with distinct prognosis and anti-tumor immunity. Further analysis suggested that purine metabolism was involved in anti-tumor immunity.

CONCLUSIONS:

This study confirmed the importance of metabolism-related pathways and in particular purine metabolism in the tumorigenesis, prognosis and anti-tumor immunity of COAD. We identified a 6-gene prognostic signature comprised of EPHX2, GPX3, PTGDS, NAT2, ACOX1 and CPT2. In addition, four potential immune-metabolic checkpoints (GUCY1A1, GUCY1B1, PDE1A and PDE5A) were identified, which could be used to improve the efficacy of immunotherapy in COAD.

项与 PDE1A 相关的新闻（医药）

2022-05-05

·医药观澜

信达生物超2.6亿美元引进！新一代PDE4抑制剂在中国申报临床

5月5日，中国国家药品监督管理局药品审评中心（CDE）官网公示，UNION therapeutics和信达生物联合提交了6项orismilast缓释片的临床试验申请，并获得受理。公开资料显示，orismilast是UNION公司开发的一款下一代PDE4抑制，已获得美国FDA授予快速通道资格。2021年，信达生物通过一项超2.6亿美元的合作获得了该候选药在中国（包括中国大陆、香港、澳门和台湾地区）的独家授权。 PDE全称为磷酸二酯酶，是包括11个家族（PDE1~PDE11）的超级酶家族，可以催化第二信使cAMP和/或cGMP水解，对细胞代谢发挥重要作用。作为PDE家族的一员，PDE4可通过特异性水解cAMP而调控促炎、抗炎细胞因子的产生，从而发挥一系列作用。目前，研究人员正在开发PDE4抑制剂用于治疗多种炎症性疾病，包括银屑病、强直性脊柱炎、特应性皮炎、类风湿关节炎、系统性红斑狼疮等等。全球范围内已有多款PDE4抑制剂获批上市。公开资料显示，orismilast是一种强效和高选择性的下一代PDE4抑制剂，具有广泛的抗炎特性。该药由LEO Pharma开发，并于2020年被UNION公司获得。2021年9月，信达生物宣布与UNION公司达成一项独家授权协议。根据协议条款，信达生物将获得orismilast在中国的研究、开发和商业化独家权益。UNION公司将收到2000万美元的首付款，并有权获得累计不超过2.47亿美元的里程碑付款，以及orismilast在中国年度销售净额的特许权使用费。同时，UNION公司保留orismilast在除中国以外的全球其它地区的权益。根据UNION公司官网资料介绍，orismilast的一个潜在优势是有望在提高抗炎效力的同时减少胃肠道副作用。目前，该公司正在开发该药用于治疗特应性皮炎、银屑病、化脓性汗腺炎（HS）等适应症。2021年11月，FDA已授予orismilast快速通道资格，用于治疗中度至重度特应性皮炎。此前，orismilast已经在银屑病的口服治疗和特应性皮炎的局部治疗中产生了积极的概念验证（PoC）数据。相比其它PDE4抑制剂，orismilast对PDE4亚型B和D的高选择性和创新的缓释方法带来了优异的治疗窗口，有望带来更好的抗炎效果和耐受性。 UNION公司官网信息显示，该公司基于orsimilast开发了两个候选产品，目前均处于2期临床研究阶段：其中，UNI50001是一种口服PDE4抑制剂，拟开发用于治疗银屑病、特应性皮炎和化脓性皮炎；UNI50002是orismilast的外敷制剂，拟开发用于治疗特应性皮炎。本次，orismilast缓释片的临床试验申请获得CDE受理是该药在中国研究的一项重要进展。希望该候选药的后续临床研究顺利进行，并取得好的结果，早日为患者带来新的治疗选择。参考资料： [1] 中国国家药品监督管理局药品审评中心官网. Retrieved May 05, 2022, from https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c [2] 信达生物与UNION therapeutics达成战略合作，引进用于治疗炎症性皮肤病的下一代PDE4抑制剂. Retrieved Sep 28，2020, from https://mp.weixin.qq.com/s/jAuuplsCM_489PrChjQlFQ[3] UNION therapeutics receives FDA Fast Track designation for oral orismilast for the treatment of moderate to severe atopic dermatitis. Retrieved Nov 4，2021, from https://uniontherapeutics.com/union-therapeutics-receives-fda-fast-track-designation-for-oral-orismilast-for-the-treatment-of-moderate-to-severe-atopic-dermatitis 内容来源于网络，如有侵权，请联系删除，谢谢。

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