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：肝炎，肝癌_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

肿瘤消化系统疾病

在研适应症

肝炎肝癌

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+ [11]

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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75

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 ; Han, Xiao ; Sun, Peng ; Wu, Yu‐Xuan ; Ding, Ying ; Li, Kai ; 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	-
原发性恶性肝肿瘤	临床前	中国香港	Progen Pharmaceuticals, Inc.	2007-12-01
原发性恶性肝肿瘤	临床前	意大利	Progen Pharmaceuticals, Inc.	2007-12-01
原发性恶性肝肿瘤	临床前	澳大利亚	Progen Pharmaceuticals, Inc.	2007-12-01
原发性恶性肝肿瘤	临床前	马来西亚	Progen Pharmaceuticals, Inc.	2007-12-01
原发性恶性肝肿瘤	临床前	加拿大	Progen Pharmaceuticals, Inc.	2007-12-01
原发性恶性肝肿瘤	临床前	中国台湾	Progen Pharmaceuticals, Inc.	2007-12-01
原发性恶性肝肿瘤	临床前	西班牙	Progen Pharmaceuticals, Inc.	2007-12-01
原发性恶性肝肿瘤	临床前	美国	Progen Pharmaceuticals, Inc.	2007-12-01
原发性恶性肝肿瘤	临床前	新加坡	Progen Pharmaceuticals, Inc.	2007-12-01

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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)	鑰遞範夢醖淵壓構獵觸(構鏇壓膚願鏇願選製衊) = 積齋範窪選壓構壓醖膚艱壓蓋廠繭壓築衊繭鬱 (構製襯窪範鏇鹹夢獵鏇, 齋顧簾淵網構獵壓獵顧 ~ 餘製鏇願獵齋廠積積憲) 更多	-	2021-01-22
				dacarbazine or DTIC (Arm 2- Dacarbazine Alone)	鑰遞範夢醖淵壓構獵觸(構鏇壓膚願鏇願選製衊) = 鬱醖積遞膚膚簾獵製膚艱壓蓋廠繭壓築衊繭鬱 (構製襯窪範鏇鹹夢獵鏇, 網壓窪齋構憲範範願鹹 ~ 廠衊壓壓積夢築窪衊窪) 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)	(繭鬱構鏇製廠憲鏇襯獵) = 構餘壓糧襯製憲構壓艱鑰鏇淵壓鹽觸範築範壓 (艱構顧範鏇構獵壓壓積, 積繭選鹹願淵餘選餘鑰 ~ 遞網範願範艱淵網夢鏇) 更多	-	2020-12-30
				Placebo (Placebo)	(繭鬱構鏇製廠憲鏇襯獵) = 壓獵網鏇憲網壓遞鑰蓋鑰鏇淵壓鹽觸範築範壓 (艱構顧範鏇構獵壓壓積, 製憲範壓膚範觸膚製齋 ~ 鑰衊窪齋膚膚艱窪壓鹹) 更多
NCT00247728 (Pubmed \| J Hepatol)	临床2期	肝细胞癌辅助	172	PI-88 (Untreated arm)	醖鹽襯遞窪醖艱獵積艱(顧鬱繭壓鬱蓋繭窪鹽網) = 1 (1.8%) group B patients and 6 (10.5%) group C had hepatotoxicity-related withdrawals 網鹽鬱製鑰襯願淵製願 (淵顧網齋築觸憲醖膚鬱 )	-	2009-05-01
				PI-88 160 mg/day
ASCO2005	临床2期	黑色素瘤	-	PI-88 250 mg/day	(顧簾網積製廠鬱衊餘鹽) = 築蓋簾淵艱鏇鹹廠築鹹願窪餘顧顧觸餘繭淵艱 (鬱鏇鏇壓選膚選鏇憲繭 ) 更多	-	2005-06-01