Giripladib(Giripladib) - 药物靶点：cPLA2α_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Giripladib (USAN)

靶点

cPLA2α

作用机制

cPLA2α 抑制剂(胞内磷脂酶A2 抑制剂)

治疗领域

皮肤和肌肉骨骼疾病免疫系统疾病

在研适应症-

非在研适应症

骨关节炎膝关节炎类风湿关节炎

原研机构

Pfizer Inc.

在研机构-

非在研机构

Wyeth AB

惠氏制药有限公司Ayerst-Wyeth Pharmaceuticals, Inc.

+ [1]

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)终止

特殊审评-

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结构

分子式C41H36ClF3N2O4S

InChIKeyNHHBNHIPCSPSHQ-UHFFFAOYSA-N

CAS号865200-20-0

关联

4

项与 Giripladib 相关的临床试验

EUCTR2006-002590-44-HU / Not yet recruitingN/A

A MULTICENTER, RANDOMIZED, DOUBLE-BLIND COMPARISON OF 4 DOSEREGIMENS OF PLA-695, NAPROXEN, AND PLACEBO ADMINISTERED DAILYFOR 6 WEEKS IN SUBJECTS WITH ACTIVE OSTEOARTHRITIS OF THE KNEE

开始日期2007-01-25

申办/合作机构-

NCT00440492 / Completed临床1期

An Open-Label Study To Evaluate The Potential Pharmacokinetic Interaction Between PLA-695 And Methotrexate When Coadministered Orally To Adult Subjects With Rheumatoid Arthritis

The purpose of this study is to determine if PLA-695 changes the blood concentrations of methotrexate when administered together.

开始日期2006-12-01

申办/合作机构

Wyeth AB

NCT00396955 / Terminated临床2期

A Multicenter, Randomized, Double-Blind Comparison of 4 Dose Regimens of Pla-695, Naproxen, and Placebo Administered Daily for 6 Weeks in Subjects With Active Osteoarthritis of the Knee

Objectives: Primary:To assess the efficacy and safety of PLA-695 in subjects with active osteoarthritis (OA) of the knee.
Secondary:To determine the pharmacokinetics (PK) and pharmacodynamics (PD) of PLA-695 among dose levels. To assess health outcome measures. To assess the effect of PLA-695 on biomarkers related to clinical responses. To assess PLA-695 exposure-response relationship on PD, efficacy, and safety measures. To assess pharmacogenomics (PGX) analysis in OA.

开始日期2006-11-01

申办/合作机构

Wyeth AB

100 项与 Giripladib 相关的临床结果

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100 项与 Giripladib 相关的转化医学

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100 项与 Giripladib 相关的专利（医药）

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5

项与 Giripladib 相关的文献（医药）

2024-12-01·Medicinal Chemistry

N,N-Disubstituted 4-Sulfamoylbenzoic Acid Derivatives as Inhibitors of Cytosolic Phospholipase A2α: Synthesis, Aqueous Solubility, and Activity in a Vesicle and a Whole Blood Assay

Article

作者: Lehr, Matthias ; Fabian, Jörg ; Vilsendorf, Imke Meyer zu ; Borecki, Daniel

Background:Cytosolic phospholipase A2α (cPLA2α) is the key enzyme that initiates the arachidonic acid cascade through which pro-inflammatory lipid mediators can be formed. Therefore, cPLA2α is considered an interesting target for the development of anti-inflammatory drugs. Although several effective inhibitors of the enzyme have been developed, none of them has yet reached clinical application.Objective:Recently, we have prepared new 4-sulfamoylbenzoic acid derivatives based on a cPLA2α inhibitor found in a ligand-based virtual screening. The most effective of these compounds were now subjected to further variations in which the substitution pattern on the sulfamoyl nitrogen atom was changed.Methods:The new compounds were tested in vitro in a vesicle assay for cPLA2α inhibition as well as for their water solubility, metabolic stability, and selectivity towards related enzymes. In addition, they were evaluated ex vivo in a whole blood assay in which metabolites of the arachidonic acid cascade formed after activation of cPLA2α were quantified using a combined online dilution/ online solid phase extraction HPLC-MS method.Results:Inhibitors with submicromolar inhibitory in vitro potency were found with favourable water solubility and selectivity. However, their efficacy did not match that of the highly effective, known, structurally related cPLA2α inhibitor giripladib, which was also tested as a reference. One advantage of some of the new compounds compared to giripladib was their significantly improved water solubility. When analyzing the substances in the ex vivo whole blood assay, it was found that the obtained inhibition data correlated better with the in vivo results when the phorbol ester 12-Otetradecanoylphorbol- 13-acetate was used for activation of the enzyme in the blood cells instead of the calcium ionophore A23187.Conclusion:New compounds with good activity towards cPLA2α and reasonable physicochemical properties were identified. Overall, the results obtained could be helpful in the development of clinically applicable inhibitors of this enzyme.

2024-09-01·Journal of Lipid Research

Temporal dissociation of COX-2-dependent arachidonic acid and 2-arachidonoylglycerol metabolism in RAW264.7 macrophages

Article

作者: Rouzer, Carol A ; Mitchener, Michelle M ; Aleem, Ansari M ; Kingsley, Philip J ; Marnett, Lawrence J

Cyclooxygenase-2 converts arachidonic acid to prostaglandins (PGs) and the endocannabinoid, 2-arachidonoylglycerol (2-AG), to PG glyceryl esters (PG-Gs). The physiological function of PG biosynthesis has been extensively studied, but the importance of the more recently discovered PG-G synthetic pathway remains incompletely defined. This disparity is due in part to a lack of knowledge of the physiological conditions under which PG-G biosynthesis occurs. We have discovered that RAW264.7 macrophages stimulated with Kdo2-lipid A (KLA) produce primarily PGs within the first 12 h followed by robust PG-G synthesis between 12 h and 24 h. We suggest that the amount of PG-Gs quantified is less than actually synthesized, because PG-Gs are subject to a significant level of hydrolysis during the time course of synthesis. Inhibition of cytosolic phospholipase A2 by giripladib does not accelerate PG-G synthesis, suggesting the differential time course of PG and PG-G synthesis is not due to the competition between arachidonic acid and 2-AG. The late-phase PG-G formation is accompanied by an increase in the level of 2-AG and a concomitant decrease in 18:0-20:4 diacylglycerol (DAG). Inhibition of DAG lipases by KT-172 decreases the levels of 2-AG and PG-Gs, indicating that the DAG-lipase pathway is involved in delayed 2-AG metabolism/PG-G synthesis. These results demonstrate that physiologically significant levels of PG-Gs are produced by activated RAW264.7 macrophages well after the production of PGs plateaus.

2021-12-01·Journal of Hematology & Oncology1区 · 医学

A novel lncRNA ROPM-mediated lipid metabolism governs breast cancer stem cell properties

1区 · 医学

ArticleOA

作者: Liu, Yongcan ; Qin, Yilu ; Zhu, Pengpeng ; Teng, Yong ; Liu, Manran ; Wan, Xueying ; Sun, Yan ; Yang, Liping ; Wang, Rui ; Hou, Yixuan ; Liu, Shuiqing

AbstractBackgroundCancer stem cells (CSCs) are considered as the major cause to tumor initiation, recurrence, metastasis, and drug resistance, driving poor clinical outcomes in patients. Long noncoding RNAs (lncRNAs) have emerged as crucial regulators in cancer development and progression. However, limited lncRNAs involved in CSCs have been reported.MethodsThe novel lncROPM (a regulator of phospholipid metabolism) in breast CSCs (BCSCs) was identified by microarray and validated by qRT-PCR in BCSCs from breast cancer cells and tissues. The clinical significance of lncROPM was evaluated in two breast cancer cohorts and TANRIC database (TCGA-BRCA, RNAseq data). Gain- and loss-of-function assays were performed to examine the role of lncROPM on BCSCs both in vitro and in vivo. The regulatory mechanism of lncROPM was investigated by bioinformatics, RNA FISH, RNA pull-down, luciferase reporter assay, and actinomycin D treatment. PLA2G16-mediated phospholipid metabolism was determined by UHPLC-QTOFMS system. Cells’ chemosensitivity was assessed by CCK8 assay.ResultsLncROPM is highly expressed in BCSCs. The enhanced lncROPM exists in clinic breast tumors and other solid tumors and positively correlates with malignant grade/stage and poor prognosis in breast cancer patients. Gain- and loss-of-function studies show that lncROPM is required for the maintenance of BCSCs properties both in vitro and in vivo. Mechanistically, lncROPM regulates PLA2G16 expression by directly binding to 3'-UTR of PLA2G16 to increase the mRNA stability. The increased PLA2G16 significantly promotes phospholipid metabolism and the production of free fatty acid, especially arachidonic acid in BCSCs, thereby activating PI3K/AKT, Wnt/β-catenin, and Hippo/YAP signaling, thus eventually involving in the maintenance of BCSCs stemness. Importantly, lncROPM and PLA2G16 notably contribute to BCSCs chemo-resistance. Administration of BCSCs using clinic therapeutic drugs such as doxorubicin, cisplatin, or tamoxifen combined with Giripladib (an inhibitor of cytoplasmic phospholipase A2) can efficiently eliminate BCSCs and tumorigenesis.ConclusionsOur study highlights that lncROPM and its target PLA2G16 play crucial roles in sustaining BCSC properties and may serve as a biomarker for BCSCs or other cancer stem cells. Targeting lncROPM-PLA2G16 signaling axis may be a novel therapeutic strategy for patients with breast cancer.

100 项与 Giripladib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D06600	-	-	DB15426

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
膝关节炎	临床2期	波兰	Wyeth AB	2006-11-01
膝关节炎	临床2期	中国香港	Wyeth AB	2006-11-01
膝关节炎	临床2期	阿根廷	Wyeth AB	2006-11-01
膝关节炎	临床2期	巴西	Wyeth AB	2006-11-01
膝关节炎	临床2期	美国	Wyeth AB	2006-11-01
膝关节炎	临床2期	匈牙利	Wyeth AB	2006-11-01
膝关节炎	临床2期	墨西哥	Wyeth AB	2006-11-01
膝关节炎	临床2期	荷兰	Wyeth AB	2006-11-01
膝关节炎	临床2期	加拿大	Wyeth AB	2006-11-01
膝关节炎	临床2期	西班牙	Wyeth AB	2006-11-01