Delving into the Latest Updates on Muparfostat sodium with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Mannopentaose phosphate sulfate, Muparfostat, Muparfostat sodium (USAN)

+ [5]

Target

VEGF-A x aFGF x bFGF

Mechanism

VEGF-A inhibitors(Vascular endothelial growth factor A inhibitors), aFGF inhibitors(Fibroblast growth factor 1 inhibitors), bFGF inhibitors(Fibroblast growth factor 2 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System Disorders

Active Indication

HepatitisLiver Cancer

Inactive Indication

Advanced cancerAdvanced Lung Non-Small Cell CarcinomaCastration-Resistant Prostatic Cancer+ [10]

Originator Organization

Australian National University Library

Active Organization

Medigen Biotechnology Corp.

Australian National University Library

Inactive Organization

Progen Pharmaceuticals, Inc.

Drug Highest PhasePhase 3

First Approval Date-

RegulationOrphan Drug (US)

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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.

01 Jun 2022·Carbohydrate ResearchQ4 · CHEMISTRY

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

Q4 · CHEMISTRY

Article

Author: 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.

10 Mar 2021·The Journal of NeuroscienceQ1 · MEDICINE

Heparanome-Mediated Rescue of Oligodendrocyte Progenitor Quiescence following Inflammatory Demyelination

Q1 · MEDICINE

Article

Author: 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 Deals associated with Muparfostat sodium

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External Link

KEGG	Wiki	ATC	Drug Bank
D10650	-	-	DB05808

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Liver Cancer	Phase 3	-	Australian National University Library	-
Hepatocellular Carcinoma	Preclinical	AU	Progen Pharmaceuticals, Inc.	01 Dec 2007
Hepatocellular Carcinoma	Preclinical	TH	Progen Pharmaceuticals, Inc.	01 Dec 2007
Hepatocellular Carcinoma	Preclinical	US	Progen Pharmaceuticals, Inc.	01 Dec 2007
Hepatocellular Carcinoma	Preclinical	CA	Progen Pharmaceuticals, Inc.	01 Dec 2007
Hepatocellular Carcinoma	Preclinical	TW	Progen Pharmaceuticals, Inc.	01 Dec 2007
Hepatocellular Carcinoma	Preclinical	SG	Progen Pharmaceuticals, Inc.	01 Dec 2007
Hepatocellular Carcinoma	Preclinical	ES	Progen Pharmaceuticals, Inc.	01 Dec 2007
Hepatocellular Carcinoma	Preclinical	MY	Progen Pharmaceuticals, Inc.	01 Dec 2007
Hepatocellular Carcinoma	Preclinical	HK	Progen Pharmaceuticals, Inc.	01 Dec 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00130442 (CTgov)	Phase 2	Metastatic melanoma	134	dacarbazine+PI-88 (Arm 1- PI-88 Plus Dacarbazine)	enbrdbsbze(nwcvygeiyy) = bfyiehlzhs iltwsjhjmh (hbwawezhzq, zawjczereo - tylzpggqpo) View more	-	22 Jan 2021
				dacarbazine or DTIC (Arm 2- Dacarbazine Alone)	enbrdbsbze(nwcvygeiyy) = uqrbpzxwii iltwsjhjmh (hbwawezhzq, xsgtojhqbq - ciiplouhnk) View more
NCT01402908 (PATRON, CTgov)	Phase 3	Hepatitis B Virus-Related Hepatocellular Carcinoma	520	PI-88 (PI-88)	qdoozsvjqd(mwtqmrdmuv) = iiipuepasc wksnwwcpec (ruvrfcbddb, ipwqamworg - xgtnvgobdp) View more	-	30 Dec 2020
				Placebo (Placebo)	qdoozsvjqd(mwtqmrdmuv) = lgruzxibfa wksnwwcpec (ruvrfcbddb, kbfnodptce - owkxjjcjmn) View more
NCT00247728 (Pubmed \| J Hepatol)	Phase 2	Hepatocellular Carcinoma Adjuvant	172	PI-88 (Untreated arm)	qkfpnxwymw(hulwuxxzzd) = 1 (1.8%) group B patients and 6 (10.5%) group C had hepatotoxicity-related withdrawals ipblcojdng (zhhqmpzfbk )	-	01 May 2009
				PI-88 160 mg/day
ASCO2005	Phase 2	Melanoma	-	PI-88 250 mg/day	(umkoxydqnl) = tjrnuswnpe sqndlfhjsq (opegptjvso ) View more	-	01 Jun 2005