磺酸化单磷酸甘露寡聚糖(Muparfostat sodium) - 药物靶点：VEGF-A x aFGF x bFGF_在研适应症：乙型肝炎，丙型肝炎，肝细胞癌_专利_临床

概要

基本信息

药物类型

聚合物

别名

Mannopentaose phosphate sulfate、Muparfostat、Muparfostat sodium (USAN)

+ [5]

靶点

VEGF-A x aFGF x bFGF

作用方式

抑制剂

作用机制

VEGF-A抑制剂(血管内皮生长因子A抑制剂)、aFGF抑制剂(成纤维细胞生长因子1抑制剂)、bFGF抑制剂(成纤维细胞生长因子2抑制剂)

治疗领域

肿瘤感染消化系统疾病

在研适应症

乙型肝炎丙型肝炎肝细胞癌+ [1]

非在研适应症

晚期癌症晚期非小细胞肺癌去势抵抗性前列腺癌+ [9]

原研机构

Australian National University Library

在研机构

基亚生物科技股份有限公司

Australian National University Library

非在研机构

Progen Pharmaceuticals, Inc.

最高研发阶段临床3期

首次获批日期-

最高研发阶段(中国)临床3期

特殊审评孤儿药 (美国)

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关联

12

项与磺酸化单磷酸甘露寡聚糖相关的临床试验

NCT01402908

/ Terminated临床3期

A Prospective, Randomized, Double-blind, Placebo Controlled, Parallel-group, International Multicenter Phase III Trial of PI-88 in the Adjuvant Treatment of Subjects With Hepatitis Virus Related HCC After Surgical Resection

The purpose of this study is to determine if PI-88 is effective and safe in patients who have had surgery to remove primary liver cancer.

开始日期2011-08-01

申办/合作机构

乾境生物技术有限公司

[+1]

EUCTR2007-005011-25-ES

/ Unknown statusN/A

A prospective, randomised, double-blind, placebo-controlled, parallel-group, international multicentre phase III trial of PI-88 in the adjuvant treatment of post-resection hepatocellular carcinomaEstudio Fase III, internacional, multicéntrico, prospectivo, aleatorizado, doble-ciego y controlado con placebo, de grupos paralelos de PI-88 en el tratamiento adyuvante de carcinoma hepatocelular post-resección (Pathway) - PATHWAY

开始日期2008-02-13

申办/合作机构-

NCT00568308

/ Terminated临床3期

A Prospective, Randomized, Double-blind, Placebo-controlled, Parallel-group, International, Multicentre Phase III Trial of PI-88 in the Adjuvant Treatment of Post-resection Hepatocellular Carcinoma

The purpose of this study is to determine if PI-88 is effective and safe in patients who have had surgery to remove primary liver cancer.

开始日期2007-12-01

申办/合作机构

Progen Pharmaceuticals, Inc.

100 项与磺酸化单磷酸甘露寡聚糖相关的临床结果

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100 项与磺酸化单磷酸甘露寡聚糖相关的转化医学

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100 项与磺酸化单磷酸甘露寡聚糖相关的专利（医药）

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74

项与磺酸化单磷酸甘露寡聚糖相关的文献（医药）

2023-07-01·British Journal of Pharmacology

The heparan sulfate mimetic Muparfostat aggravates steatohepatitis in obese mice due to its binding affinity to lipoprotein lipase

Article

作者: Sun, Hao‐Ran ; Sun, Shao‐Kun ; Zhou, Qin‐Yao ; Li, Guan‐Ting ; Li, Kai ; Sun, Peng ; Wu, Yu‐Xuan ; Ding, Ying ; Han, Xiao ; Zhang, Jia ; Ge, Yu‐Ting ; Zhu, Ya‐Ting ; Chang, Xiao‐Ai

Background and PurposeHeparanase is the only confirmed endoglycosidase that cleaves heparan sulfate (HS), a ubiquitous glycosaminoglycan with various essential roles in multiple pathological processes. Thus, the development of heparanase inhibitors has become an attractive strategy for drug discovery, especially in tumour therapy, in which HS mimetics are the most promising compounds. The various biological effects of heparanase also suggest a role for HS mimetics in many non‐cancer indications, such as type 1 diabetes. However, the potential benefits of HS mimetics in obesity‐related type 2 diabetes have not been elucidated.Experimental ApproachIn this study, we investigated muparfostat (PI‐88), a developed HS mimetic currently enrolled in Phase III clinical trials, in obese mouse models and in vitro cultured murine hepatocytes.Key ResultsDaily administration of muparfostat for 4 weeks caused hyperlipidaemia and aggravated hepatic steatosis in obese mice models, but not in lean animals. In cultured hepatocytes, muparfostat did not alter lipid accumulation. Acute tests suggested that muparfostat binds to lipoprotein lipase in competition with HS on vascular endothelial cell surfaces, thereby reducing the degradation of circulating triglycerides by lipoprotein lipase and subsequent uptake of fatty acids into vascular endothelial cells and causing hyperlipidaemia. This hyperlipidaemia aggravates hepatic steatosis and causes liver injury in muparfostat‐treated obese mice.Conclusions and ImplicationsThe binding activity of HS mimetics to lipoprotein lipase should be investigated as an additional pharmacological effect during heparanase inhibitor drug discovery. This study also provides novel evidence for an increased risk of drug‐induced liver injury in obese individuals.

2022-06-01·Carbohydrate Research4区 · 化学

Access to n-pentenyl tetra- and pentasaccharide analogues of the antitumor drug PI-88 based on 1,2-methyl orthoester glycosyl donors

4区 · 化学

Article

作者: López, J Cristobal ; Ventura, Juan ; Uriel, Clara ; Gómez, Ana M

Convergent synthetic routes to PI-88 tetra- and pentasaccharide-component analogues, have been developed featuring regioselective glycosylations of mannose-polyol n-pentenyl glycosides (NPG) acceptors with 1,2-methyl orthoesters (MeOE) glycosyl donors.

2021-03-10·The Journal of Neuroscience1区 · 医学

Heparanome-Mediated Rescue of Oligodendrocyte Progenitor Quiescence following Inflammatory Demyelination

1区 · 医学

Article

作者: Saraswat, Darpan ; Tripathi, Ajai ; Broome, Jacqueline ; Polanco, Jessie J ; Sim, Fraser J ; Ravichandar, Roopa ; Hurley, Edward ; Dutta, Ranjan ; Feltri, M Laura ; Welliver, R Ross

The proinflammatory cytokine IFN-γ, which is chronically elevated in multiple sclerosis, induces pathologic quiescence in human oligodendrocyte progenitor cells (OPCs) via upregulation of the transcription factor PRRX1. In this study using animals of both sexes, we investigated the role of heparan sulfate proteoglycans in the modulation of IFN-γ signaling following demyelination. We found that IFN-γ profoundly impaired OPC proliferation and recruitment following adult spinal cord demyelination. IFN-γ-induced quiescence was mediated by direct signaling in OPCs as conditional genetic ablation ofIFNγR1(Ifngr1) in adult NG2+OPCs completely abrogated these inhibitory effects. Intriguingly, OPC-specific IFN-γ signaling contributed to failed oligodendrocyte differentiation, which was associated with hyperactive Wnt/Bmp target gene expression in OPCs. We found that PI-88, a heparan sulfate mimetic, directly antagonized IFN-γ to rescue human OPC proliferation and differentiationin vitroand blocked the IFN-γ-mediated inhibitory effects on OPC recruitmentin vivo. Importantly, heparanase modulation by PI-88 or OGT2155 in demyelinated lesions rescued IFN-γ-mediated axonal damage and demyelination. In addition to OPC-specific effects, IFN-γ-augmented lesions were characterized by increased size, reactive astrogliosis, and proinflammatory microglial/macrophage activation along with exacerbated axonal injury and cell death. Heparanase inhibitor treatment rescued many of the negative IFN-γ-induced sequelae suggesting a profound modulation of the lesion environment. Together, these results suggest that the modulation of the heparanome represents a rational approach to mitigate the negative effects of proinflammatory signaling and rescuing pathologic quiescence in the inflamed and demyelinated human brain.SIGNIFICANCE STATEMENTThe failure of remyelination in multiple sclerosis contributes to neurologic dysfunction and neurodegeneration. The activation and proliferation of oligodendrocyte progenitor cells (OPCs) is a necessary step in the recruitment phase of remyelination. Here, we show that the proinflammatory cytokine interferon-γ directly acts on OPCs to induce pathologic quiescence and thereby limit recruitment following demyelination. Heparan sulfate is a highly structured sulfated carbohydrate polymer that is present on the cell surface and regulates several aspects of the signaling microenvironment. We find that pathologic interferon-γ can be blocked by modulation of the heparanome following demyelination using either a heparan mimetic or by treatment with heparanase inhibitor. These studies establish the potential for modulation of heparanome as a regenerative approach in demyelinating disease.

100 项与磺酸化单磷酸甘露寡聚糖相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10650	-	-	DB05808

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
肝癌	临床3期	-	Australian National University Library	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00130442 (CTgov)	临床2期	转移性黑色素瘤	134	dacarbazine+PI-88 (Arm 1- PI-88 Plus Dacarbazine)	夢壓糧壓鹽製鬱繭壓餘(鏇壓襯簾範遞簾鹹築製) = 鹹選膚構觸顧憲廠鹹壓製遞鏇夢獵蓋獵餘夢蓋 (醖願繭糧鏇製窪繭淵襯, 膚遞襯觸構鹹蓋鏇範積 ~ 簾顧淵鑰艱網醖齋製夢) 更多	-	2021-01-22
				dacarbazine or DTIC (Arm 2- Dacarbazine Alone)	夢壓糧壓鹽製鬱繭壓餘(鏇壓襯簾範遞簾鹹築製) = 餘獵鏇夢製積餘選選鬱製遞鏇夢獵蓋獵餘夢蓋 (醖願繭糧鏇製窪繭淵襯, 願範醖築艱製獵鹹鹹壓 ~ 淵蓋廠艱壓醖鑰製餘製) 更多
NCT01402908 (PATRON, CTgov)	临床3期	乙型肝炎病毒相关肝细胞癌	520	PI-88 (PI-88)	(襯醖遞蓋淵鬱餘襯壓繭) = 積獵觸醖艱鏇鹹構鏇蓋鏇鑰憲選獵簾鏇獵選網 (鑰築顧鹹鹽網構獵鏇鑰, 醖顧膚憲廠壓觸齋膚鑰 ~ 衊夢憲製簾範餘顧獵膚) 更多	-	2020-12-30
				Placebo (Placebo)	(襯醖遞蓋淵鬱餘襯壓繭) = 艱鹽鏇壓餘範遞鬱觸觸鏇鑰憲選獵簾鏇獵選網 (鑰築顧鹹鹽網構獵鏇鑰, 淵獵顧憲蓋願襯膚鑰廠 ~ 衊選憲憲夢糧蓋簾廠蓋) 更多
NCT00247728 (Pubmed \| J Hepatol)	临床2期	肝细胞癌辅助	172	PI-88 (Untreated arm)	餘繭獵鹽襯顧餘襯簾齋(鬱網簾廠簾壓蓋蓋膚願) = 1 (1.8%) group B patients and 6 (10.5%) group C had hepatotoxicity-related withdrawals 憲夢鹽鑰餘願淵鏇觸憲 (範壓鹽糧廠糧鏇鏇簾簾 )	-	2009-05-01
				PI-88 160 mg/day
ASCO2005	临床2期	黑色素瘤	-	PI-88 250 mg/day	(遞遞範製築醖壓蓋製觸) = 簾膚廠鹽獵艱簾齋鹹餘遞積廠製齋壓壓鑰繭繭 (壓膚積鑰網鬱鹽膚膚遞 ) 更多	-	2005-06-01