更新于：2024-11-01

PDE4B

更新于：2024-11-01

基本信息

别名

cAMP-specific 3',5'-cyclic phosphodiesterase 4B、DPDE4、PDE IVB

+ [7]

简介

Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes (PubMed:15260978). May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.

关联

项与 PDE4B 相关的药物

Difamilast

靶点

PDE4B

作用机制

PDE4B抑制剂

在研机构

Otsuka Pharmaceutical Co., Ltd. [+1]

原研机构

Otsuka Pharmaceutical Co., Ltd.

在研适应症

特应性皮炎

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

日本

首次获批日期2021-09-27

Ademetionine 1,4-Butanedisulfonate

丁二磺酸腺苷蛋氨酸

靶点

PDE4B

作用机制

PDE4B抑制剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

意大利

首次获批日期1975-01-01

Theobromin

可可碱

靶点

A1R x A2aR x PDE4B

作用机制

A1R拮抗剂 [+2]

在研机构

石药集团新诺威制药股份有限公司

原研机构

石药集团新诺威制药股份有限公司

在研适应症

心血管疾病

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区-

首次获批日期1800-01-20

137

项与 PDE4B 相关的临床试验

CTRI/2024/10/075029 / Not yet recruiting临床3期

An open-label extension trial of the long-term safety and efficacy of BI 1015550 taken orally in patients with idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) - FIBRONEER™-ON

开始日期2025-02-07

申办/合作机构

Boehringer Ingelheim GmbH

[+1]

NCT06663605 / Recruiting临床1期

A Phase 1, Double-Blind, Placebo-Controlled, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of PALI-2108 in Healthy Volunteers and Open-Label Study of a Patient Cohort With Ulcerative Colitis

PALI-2108 is a new oral medication designed to treat ulcerative colitis (UC) by targeting the intestines. It works as a phosphodiesterase-4 (PDE4) inhibitor prodrug, meaning it becomes active only after being processed by bacteria in the colon. This targeted approach reduces the risk of side effects that can occur with other medications that affect the entire body.
Recent studies have shown that patients with active UC, especially those with moderate to severe symptoms, have higher levels of PDE4 and related biomarkers. These biomarkers are linked to the severity of their disease, suggesting that inhibiting PDE4 could help manage UC effectively.
The goal of this Phase 1 study is to evaluate the safety, tolerability, and how the body processes (pharmacokinetics) and responds to (pharmacodynamics) PALI-2108 in healthy volunteers. Although there are already PDE4 inhibitors on the market, PALI-2108 is a completely new compound that has not been tested in humans before. The study will involve two parts: first, participants will receive single doses of the drug, and then, in the second part, they will take it twice a day for seven days.
The twice-daily dosing schedule is designed to maximize drug exposure in the colon. The investigators will also investigate how food affects the drug's absorption.
Additionally, a small group of stable UC patients will be included in the study. These patients will also take PALI-2108 for seven days, allowing us to compare the safety and drug processing between healthy individuals and those with UC. The investigators will monitor important health markers and conduct tests on colon tissue to see how well the drug works and if it causes any changes in the tissue.
Including UC patients early in this research is important for understanding how the drug performs in real-world conditions. This data will help refine our approach to identify which patients might benefit most from PALI-2108 in future studies.
Overall, this study aims to gather crucial information about PALI-2108's safety and effectiveness, paving the way for new treatment options for patients with ulcerative colitis.

开始日期2024-11-05

申办/合作机构

Palisade Bio, Inc.

[+1]

CTRI/2024/09/074413 / Not yet recruiting临床4期

A Prospective, Open-Label, Single-Arm, Pilot Study To Evaluate The Effectiveness Of Oral Ademetionine In Patients With Alcoholic Liver Disease (ALD) In Indian Scenario (ADEM-D22-0319) - NIL

开始日期2024-10-15

申办/合作机构-

100 项与 PDE4B 相关的临床结果

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100 项与 PDE4B 相关的转化医学

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0 项与 PDE4B 相关的专利（医药）

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656

项与 PDE4B 相关的文献（医药）

2024-11-01·Phytomedicine

Hua-Shi-Bai-Du decoction inactivates NLRP3 inflammasome through inhibiting PDE4B in macrophages and ameliorates mouse acute lung injury

Article

作者: Li, Ximeng ; Qi, Yun ; Gao, Yuan ; Liu, Zhuangzhuang ; Cai, Min ; Yan, Jingjing ; Li, Wenjing ; Zang, Chenchen ; Cai, Runlan

BACKGROUNDHua-Shi-Bai-Du decoction (HSBD) exerts significant effects on the prevention and treatment of COVID-19 in China. The activation of the NLRP3 inflammasome of macrophages plays a vital role in COVID-19 pathology. However, no previous studies have focused on this pathological process to explore the effect of HSBD.PURPOSEOur aim is to uncover the effect of HSBD on NLRP3 inflammasome activation and the underlying mechanisms.METHODSThe NLRP3-activated J774A.1 cells primed by LPS and activated by nigericin/ATP/MSU were used to evaluate NLRP3 activation in vitro. ASC oligomerization and speck formation were assessed by western blot and immunofluorescence imaging. Intracellular K⁺ levels were determined by the colorimetric assay. Mitochondrial ROS (mtROS) level was detected by the flow cytometry and the fluorescence spectrophotometry. The intracellular cAMP level was determined by chemiluminescence method and ELISA, while phosphodiesterase (PDE) activity was measured using the fluorescent substrate MANT-cAMP. siRNA was applied to knockdown PDE4B. Two in vivo mouse models, MSU-induced peritonitis and LPS-induced acute lung injury (ALI), were used to evaluate the effects of HSBD on IL-1β and other inflammatory cytokines. Pathological changes in lung tissue were observed by histopathological examination.RESULTSHSBD not only decreased supernatant IL-1β, caspase-1 p20, and cleaved gasdermin D (GSDMD) in NLRP3-activated J774A.1 cells, but also reduced IL-1β in the peritoneal lavage fluid of mice with MSU-induced peritonitis, demonstrating the suppressive effect on NLRP3 inflammasome activation. The mechanism study showed that HSBD blocked ASC oligomerization and speck formation without affecting K⁺ efflux or mtROS production. Furthermore, it prevented the decrease of intracellular cAMP by inhibiting PDE4B activity. And in the PDE4B-deficient cells, its suppressive effect on IL-1β release was abolished. In LPS-induced ALI mice, oral administration of HSBD decreased several proinflammatory cytokines (IL-1β, IL-6, TNF-α, and CXCL-1) and attenuated the pathological damage to the lung.CONCLUSIONHSBD suppresses the activation of NLRP3 inflammasome by inhibiting PDE4B activity to counteract the decrease of intracellular cAMP, thereby blocking ASC oligomerization in macrophages. Our findings may provide new insight into the clinical effets of HSBD for the treatment of COVID-19.

2024-10-23·The Journal of Neuroscience

PDE4B Missense Variant Increases Susceptibility to Post-traumatic Stress Disorder-Relevant Phenotypes in Mice

Article

作者: Amstislavskaya, Tamara G ; Clapcote, Steven J ; Woodgett, James R ; Cameron, Ryan T ; Baillie, George S ; Petrova, Ekaterina S ; Gondo, Yoichi ; Li, Shupeng ; Elliott, Christina ; Lipina, Tatiana V ; Mullins, Jonathan G L ; McGirr, Alexander

Large-scale genome-wide association studies (GWASs) have associated intronic variants in PDE4B , encoding cAMP-specific phosphodiesterase-4B (PDE4B), with increased risk for post-traumatic stress disorder (PTSD), as well as schizophrenia and substance use disorders that are often comorbid with it. However, the pathophysiological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effects of PDE4B variation on phenotypes with translational relevance to psychiatric disorders, we focused on PDE4B missense variant M220T, which is present in the human genome as rare coding variant rs775201287. When expressed in HEK-293 cells, PDE4B1-M220T exhibited an attenuated response to a forskolin-elicited increase in the intracellular cAMP concentration. In behavioral tests, homozygous Pde4bM220T male mice with a C57BL/6JJcl background exhibited increased reactivity to novel environments, startle hyperreactivity, prepulse inhibition deficits, altered cued fear conditioning, and enhanced spatial memory, accompanied by an increase in cAMP signaling pathway-regulated expression of BDNF in the hippocampus. In response to a traumatic event (10 tone–shock pairings), neuronal activity was decreased in the cortex but enhanced in the amygdala and hippocampus of Pde4bM220T mice. At 24 h post-trauma, Pde4bM220T mice exhibited increased startle hyperreactivity and decreased plasma corticosterone levels, similar to phenotypes exhibited by PTSD patients. Trauma-exposed Pde4bM220T mice also exhibited a slower decay in freezing at 15 and 30 d post-trauma, demonstrating enhanced persistence of traumatic memories, similar to that exhibited by PTSD patients. These findings provide substantive mouse model evidence linking PDE4B variation to PTSD-relevant phenotypes and thus highlight how genetic variation of PDE4B may contribute to PTSD risk.

2024-10-01·Chemico-Biological Interactions

Phosphodiesterase 4 is overexpressed in human keloids and its inhibition reduces fibroblast activation and skin fibrosis

Article

作者: Milara, Javier ; Marín, Severiano ; Roger, Inés ; Cortijo, Julio ; Montero, Paula ; Tenor, Herman ; Ribera, Pilar

There is a pressing medical need for improved treatments in skin fibrosis including keloids and hypertrophic scars (HTS). This study aimed to characterize the role of phosphodiesterase 4 (PDE4), specifically PDE4B in fibrotic skin remodeling in vitro and in vivo. In vitro, effects of PDE4A-D (Roflumilast) or PDE4B (siRNA) inhibition on TGFβ1-induced myofibroblast differentiation and dedifferentiation were studied in normal (NHDF) and keloid (KF) human dermal fibroblasts. In vivo, the role of PDE4 on HOCl-induced skin fibrosis in mice was addressed in preventive and therapeutic protocols. PDE4B (mRNA, protein) was increased in Keloid > HTS compared to healthy skin and in TGFβ-stimulated NHDF and KF. In Keloid > HTS, collagen Iα1, αSMA, TGFβ1 and NOX4 mRNA were all elevated compared to healthy skin confirming skin fibrosis. In vitro, inhibition of PDE4A-D and PDE4B similarly prevented TGFβ1-induced Smad3 and ERK1/2 phosphorylation and myofibroblast differentiation, elevated NOX4 protein and proliferation in NHDF. PDE4A-D inhibition enabled myofibroblast dedifferentiation and curbed TGFβ1-induced reactive oxygen species and fibroblast senescence. In KF PDE4A-D inhibition restrained TGFβ1-induced Smad3 and ERK1/2 phosphorylation, myofibroblast differentiation and senescence. Mechanistically, PDE4A-D inhibition rescued from TGFβ1-induced loss in PPM1A, a Smad3 phosphatase. In vivo, PDE4 inhibition mitigated HOCl-induced skin fibrosis in mice in preventive and therapeutic protocols. The current study provides novel evidence evolving rationale for PDE4 inhibitors in skin fibrosis (including keloids and HTS) and delivered evidence for a functional role of PDE4B in this fibrotic condition.

项与 PDE4B 相关的新闻（医药）

2024-10-16

·新药前沿

海思科新药靶点布局大梳理，与恒瑞严重“撞车”？

在业内，海思科素有“小恒瑞”的称号。关注新药前沿微信公众号的朋友可能也注意到，在多个新靶点药物开发的介绍中，海思科与恒瑞往往“如影随形”。不可否认，国内能与恒瑞庞大的创新药管线匹敌者寥寥可数。而资本市场给予海思科的定位是特色创新药小龙头。可见二者在创新药战略布局还有巨大的差异。尽管如此，通过对海思科新药靶点布局的梳理发现，其与恒瑞发生“撞车”的比例达到了50%。在海思科的新药管线中，其开发的项目涉及到14个靶点，海思科与恒瑞正在（或以前）有布局的相同靶点至少有7个。海思科已获批准上市创新药品种中，麻醉镇痛药物γ-氨基丁酸A （GABAa）受体激动剂思舒宁（环泊酚注射液）和糖尿病药物DPP4抑制剂倍长平（考格列汀片），而恒瑞分别同样具有已上市的瑞倍宁（注射用甲苯磺酸瑞马唑仑）和瑞泽唐（磷酸瑞格列汀片）与其对标。海思科刚获批的电压敏感型钙离子通道（VGCC）调节剂思美宁（苯磺酸克利加巴林胶囊）是国内首款、全球第二款第三代钙离子通道调节剂，而恒瑞并未在该靶点进行项目布局。而在研发项目中，尤其是非肿瘤领域的疼痛和呼吸疾病，海思科与恒瑞相同靶点项目开发“撞车”尤为严重。在疼痛领域，恒瑞曾放弃了已完成Ⅲ期临床试验的选择性外周κ阿片受体（KOR）激动剂SHR0410，而海思科的HSK21542已推进到上市申请（NDA）阶段。恒瑞在该靶点的战略性放弃可能与其主力推动其μ阿片受体（MOR）偏向性小分子激动剂艾苏特（富马酸泰吉利定注射液）有关。尽管KOR激动剂在克服阿片类成瘾性方面具有优势，但在止痛效果上可能不如MOR激动剂。 NaV1.8抑制剂作为疼痛治疗新型热门靶点，恒瑞放弃已完成Ⅱ期的HRS4800后进而开发新一代NaV1.8抑制剂HRS-2129，并于上个月底推进到Ⅰ期。而今年7月份公布的一件海思科申请PCT专利同样对新一代NaV1.8抑制剂进行了布局。在呼吸疾病领域，海思科非囊性纤维化支气管扩张症DPP1抑制剂HSK31858已通过对外权益许可为该公司带来收益，目前也进入到Ⅲ期临床试验。而恒瑞的RSS0343片在今年3月才开启Ⅰ期临床试验。而慢性阻塞性肺病（COPD）PDE3/4双重抑制剂的开发中，恒瑞的HRS-9821和海思科的HSK39004都于近期推进到到Ⅰ期临床试验中，旗鼓相当。海思科似乎已经放弃了特发性纤维化ATX抑制剂FTP198，而恒瑞今年7月启动了其开发的HRS-9813治疗特发性肺纤维化的Ⅰ期临床试验。不过海思科已转而开发该领域同样热门的靶点项目PDE4B抑制剂HSK44459，也已进入到Ⅰ期。此外，两家公司可能还在开发甲状腺激素β受体（THR-β）激动剂项目。当然，海思科与恒瑞在疼痛和呼吸疾病领域靶点布局的高重合性并非偶然。与肿瘤、自身免疫疾病靶点层出不穷相比，疼痛和呼吸疾病领域新靶点显得寥若星辰。换位思考，而同时被海思科与恒瑞这两家公司看上的靶点也许正说明了其在中国市场未来的潜力。不过，多个靶点并非仅有海思科与恒瑞在开发，可能还有更多的其他follow者。本文由「新药前沿」微信公众号根据公开资料整理编辑，欢迎个人转发至朋友圈。媒体或机构转载授权请在「新药前沿」微信公众号留言公众号名称，审核通过后开通白名单获取转载授权，转载请标识来源。免责声明：本文仅作信息交流之目的，非投资建议或者治疗方案推荐，「新药前沿」微信公众号不对任何主体因使用本文内容而导致的任何损失承担责任。限于作者水平和专业知识所限，如有谬误，欢迎指正！

临床3期上市批准临床2期

2024-10-14

·GlobeNewswire-Health Care

Palisade Bio Cleared by Health Canada to Commence Phase 1 Clinical Study for Lead Program, PALI-2108 for the Treatment of Ulcerative Colitis (UC)

– Company has received a No Objection Letter from Health Canada in response to submission of its Phase 1 Clinical Trial Application (CTA) – The study is a Phase 1 Single Ascending Dose (SAD) /Multiple Ascending Dose (MAD) and food effects (FE) and includes multiple dose treatment of UC patients; Global UC market is expected to grow to nearly $10 Billion by 2028 Oct. 10, 2024 -- Palisade Bio, Inc. (Nasdaq: PALI) (“Palisade,” “Palisade Bio” or the “Company”), a biopharmaceutical company focused on developing and advancing novel therapeutics for patients living with autoimmune, inflammatory, and fibrotic diseases, today announced that it has received a No Objection Letter from Health Canada for its Phase 1 human clinical study for PALI-2108 for the treatment of UC. “We are thrilled to receive a No Objection Letter from Health Canada in response to our Clinical Trial Application. This achievement marks the most important milestone to date for our PALI-2108 development program. We continue to believe in the potential of PALI-2108 to be the first approved PDE4 inhibitor for UC and more importantly, provide a much-needed effective and safe solution for UC patients still experiencing significant medical need. Our team remains focused on continuing preparations for the initiation of our Phase 1 clinical trial which is on track to commence before year end,” commented J.D. Finley, Chief Executive Officer. PALI-2108 is an orally administered PDE4 inhibitor prodrug which is locally bioactivated in the colon and is in development for patients affected by UC. The Phase 1 study will evaluate PALI-2108 in a single-center, double-blind, placebo-controlled study focused on safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers, alongside an open-label study involving a patient cohort with UC. As previously announced, the Company has established dose levels and trial design for PALI-2108 and plans to enroll approximately 90 patients across the SAD, FE, MAD and UC cohorts. “Patients are actively seeking new and more effective treatment options for their ulcerative colitis. Currently, existing therapies achieve complete remission in fewer than a quarter of patients, and many of the most effective treatments involve injections or carry black box warnings due to serious side effects. A safe and effective oral medication for UC would be highly desirable for the majority of patients,” said Florian Rieder, MD, a member of the Palisade Bio Clinical Advisory Board and Associate Staff in the Department of Gastroenterology, Hepatology, and Nutrition, as well as an Investigator in the Department of Pathobiology at the Cleveland Clinic. The primary objective of the study will be to assess the safety and tolerability of single (healthy subjects) and repeated (healthy subjects and UC patients) oral doses of PALI-2108. Secondary objectives include determining the plasma, urinary, and fecal (MAD healthy subjects and UC patients only) pharmacokinetics (PK) of PALI-2108 and its metabolites following PALI-2108 single (healthy subjects) and repeated (healthy subjects and UC patients) oral doses, as well as the effect of food on the PK of PALI-2108 and its metabolites following a single oral dose in healthy subjects. Exploratory objectives will include PDE4-related pharmacodynamic (PD) biomarkers, concentrations of the active form of PALI-2108, high sensitivity C-reactive protein (hsCRP), fecal calprotectin (CalPro), colonic tissue Absolute Lymphocyte Count (ALC), Modified Mayo score, as well as colonic histological changes in UC patients following repeated PALI-2108 oral doses. Preparations for the clinical study remain ongoing and the Company is on track commence site initiation and enrollment for the study before year end. Palisade Bio is a biopharmaceutical company focused on developing and advancing novel therapeutics for patients living with autoimmune, inflammatory, and fibrotic diseases. The Company believes that by using a targeted approach with its novel therapeutics it will transform the treatment landscape. For more information, please go to www.palisadebio.com. The content above comes from the network. if any infringement, please contact us to modify.

临床研究

2024-10-10

·新药前沿

“有新无创”式中国“新药”的窘境

关注新药，直击前沿！没有对比就没有伤害！更重要的是，没有对比，就难以正视自己的差距，进而寻求破解之策！分享2篇近期刊发于Nature Reviews Drug Discovery的文章图表数据：第一篇：Development of Chinese innovative drugs in the USA 2007-2023年中国创新药（innovative drugs）开展临床试验情况（来源于ClinicalTrials.gov）。 1、启动临床试验数量 2、申办者分布情况 3、临床试验开展现状 4、临床试验成功率在此期间，在美国进行试验的6种中国创新药物获得了美国药品食品监督管理局（FDA）的批准，分别为：泽布替尼（zanubrutinib, 2019年首次批准）、西达基奥伦塞（ciltacabtagene autoleucel, 2022）、本维莫德（benvitimod, 2022）、特瑞普利单抗（toripalimab, 2023）、呋喹替尼（fruquintinib, 2023）和艾贝格司亭α（efbemalenograstim alfa, 2023）第二篇：Comparative analysis of FDA approvals by top 20 pharma companies (2014-2023) 在2014年至2023年：FDA批准了全球TOP 20制药公司176种新药。其中83种属于同类首创药物（first-in-class）。这也就意味着，过去10年全球TOP 20制药公司获得FDA批准新药平均数量8.8种（剔除通过上市后收购药物获得这一数字为7.15种）。而且还是在TOP 20制药公司获批新药份额从72%（2014年）下降到40%（2023年）取得的数据。思考：很显然，中国创新药近年来尽管取得长足进展，但是：国内仍存在许多Pharma或者Biotech仅仅是通过follow方式Me-too项目的现象，这种“有新无创”式的“新药”基本不可能跨出国门（从国内众多“新药”的研发区域布局如临床试验开展和专利申请等可知）。更何况，全球领先医药公司在新药开发过程中项目升级迭代导致国内企业follow错误难以调转船头也时有发生。在药物研发领域，做到“新”是很容易的事情，尤其是在浩瀚的化合物中筛选不同结构，但最终能否实现具有自身临床优势的“创造性“才是关键。中国医药行业经历2016年仿制药大洗牌，再到本轮资本寒冬下的创新药大洗牌之后，或许才会真正起航。而谁会是经历两轮洗礼之后的幸存者呢？！ “新药前沿”格言大型制药公司领导者必须解决六个研发关键问题：清晰度、灵活性、责任、团队承诺、标准和奖励。往期推荐 01 Nav1.8抑制剂fast-follow者恒瑞快速调转船头 02 吸入PDE3/4抑制剂fast-follow凑齐3家：正大天晴领跑，恒瑞延缓后被海思科追赶 03 First in Class心衰靶点RXFP1诺华、BMS失利后，礼来、AZ继续前行 04 DPP1抑制剂fast-follow者海思科的完美“变现” 05 神经疼痛新靶点AAK1：IIa期POC已成功，引国内多家公司fast-follow布局 06 让癌细胞分裂时“毙命”，KIF18A靶点启航 07 PDE4B抑制剂fast-follow者海思科和人福，紧追勃林格殷格翰 08 IPF也疯狂：新药开发“三剑客”突围 09 SHP2遭遇大药企“退货潮”：罗氏、赛诺菲、艾伯维、BMS 10 百时美施贵宝新药开发的毒理学评价之道 11 恒瑞急性疼痛新药HRS-2129获批临床，布局新一代NaV1.8抑制剂，兵贵神速本文由「新药前沿」微信公众号根据公开资料整理编辑，欢迎个人转发至朋友圈。媒体或机构转载授权请在「新药前沿」微信公众号留言公众号名称，审核通过后开通白名单获取转载授权，转载请标识来源。免责声明：本文仅作信息交流之目的，非投资建议或者治疗方案推荐，「新药前沿」微信公众号不对任何主体因使用本文内容而导致的任何损失承担责任。限于作者水平和专业知识所限，如有谬误，欢迎指正！

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