Delving into the Latest Updates on Oltipraz with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

Nrf2

Action

stimulants

Mechanism

Nrf2 stimulants(Nuclear factor erythroid 2-related factor 2 stimulants)

Therapeutic Areas

NeoplasmsDigestive System Disorders

Active Indication

Colonic Cancer

Inactive Indication

Liver CirrhosisMetabolic dysfunction-associated steatotic liver diseaseNonalcoholic Steatohepatitis

Originator Organization

Pfizer Inc.

Active Organization

University of Pennsylvania

Inactive Organization

Pfizer Inc.

Pharma King Co., Ltd.Canopus Holding SA

+ [1]

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC8H6N2S3

InChIKeyCKNAQFVBEHDJQV-UHFFFAOYSA-N

CAS Registry64224-21-1

Dithiolethiones, a novel class of adenosine monophosphate-activated protein kinase (AMPK) activators, prevent insulin resistance through AMPK-dependent p70 ribosomal S6 kinase-1 (S6K1) inhibition. And it is well known that the modulation of S6K1 by oltipraz inhibited the development of insulin resistance and hyperglycemia through the AMPK-S6K1 pathway.Also some research reported that LXRg (a member of the nuclear hormone receptor)-mediated increases in SREBP-1c (the sterol regulatory element-binding protein-1c gene) promote the expression of lipogenic genes and enhance fatty acid synthesis and oltipraz inhibits LXRg and SREBP-c. Therefore, Oltipraz inhibits fatty acid synthesis through AMPK-S6K1 pathway and LXRg-SREBP-1c pathway in liver.

Start Date01 Feb 2014

Sponsor / Collaborator

Pharma King Co., Ltd.

NCT01373554

/ CompletedPhase 2

A Multicenter, Randomized, Double-blind, Placebo-controlled, A Multicenter, Randomized, Double-blind, Placebo-controlled, 3 Parallel Groups, Phase 2 Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Oltipraz in Patients With Non-alcoholic Fatty Liver Disease (Except Liver Cirrhosis)

Dithiolethiones, a novel class of adenosine monophosphate-activated protein kinase (AMPK) activators, prevent insulin resistance through AMPK-dependent p70 ribosomal S6 kinase-1 (S6K1) inhibition. And it is well known that the modulation of S6K1 by oltipraz inhibited the development of insulin resistance and hyperglycemia through the AMPK-S6K1 pathway.Also some research reported that LXRg (a member of the nuclear hormone receptor)-mediated increases in SREBP-1c (the sterol regulatory element-binding protein-1c gene) promote the expression of lipogenic genes and enhance fatty acid synthesis and oltipraz inhibits LXRg and SREBP-c. Therefore, Oltipraz inhibits fatty acid synthesis through AMPK-S6K1 pathway and LXRg-SREBP-1c pathway in liver.

Start Date01 May 2011

Sponsor / Collaborator

Pharma King Co., Ltd.

100 Clinical Results associated with Oltipraz

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100 Translational Medicine associated with Oltipraz

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100 Patents (Medical) associated with Oltipraz

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683

Literatures (Medical) associated with Oltipraz

01 Feb 2025·Brain, Behavior, and Immunity

Unraveling morphine tolerance: CCL2 induces spinal cord apoptosis via inhibition of Nrf2 signaling pathway and PGC-1α-mediated mitochondrial biogenesis

Article

Author: Xiaoling, Peng ; Jie, Liu ; Jihao, Ren ; Feng, Gao ; Wei, Zhao ; Zheng, Li ; Jie, Ju

BACKGROUNDMorphine effectively relieves severe pain but leads to analgesic tolerance with long-term use.The molecular mechanisms underlying morphine tolerance remain incompletely understood. Existing literature suggests that chemokine CCL2, present in the spinal cord, plays a role in central nervous system inflammation, including neuropathic pain. Nevertheless, the precise mechanism through which CCL2 mediates morphine tolerance has yet to be elucidated. Consequently, this study aims to investigate the molecular pathways by which CCL2 contributes to the development of morphine analgesic tolerance.METHODSRats were administered intrathecal morphine (10 μg/5 μl) twice a day for seven consecutive days to induce a model of morphine nociceptive tolerance. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression levels of CCL2 and its related mechanism molecules. Immunofluorescence was used to detect the localization of CCL2 in the spinal cord. Intrathecal injections of inhibitors or agonists to artificially regulate the expression of relevant molecules. The thermal tail-flick experiment was performed to evaluate morphine tolerance in rats.RESULTSMorphine-induced CCL2 expression was significantly increased in spinal cord, while conversely, the expressions of Nrf2 and PGC-1a were downregulated. Immunofluorescence showed that the enhanced immune response of CCL2 mainly co-localized with neurons. In vivo, we confirmed that intrathecally injection of CCL2 inhibitor Bindarit could effectively alleviate the occurrence of apoptosis and alleviate morphine tolerance. Similarly, pretreatment with Nrf2 signaling pathway agonist Oltipraz and PGC-1α agonist ZLN005 also achieved similar results, respectively. ROS Fluorescence Assay Kit indicated that increasing the expression of PGC-1α could alleviate the occurrence of apoptosis by reducing the level of ROS.CONCLUSIONOur data emphasize that chemokine CCL2 inhibited the Nrf2 signaling pathway and PGC-1α-mediated mitochondrial biogenesis, alleviating the occurrence of apoptosis in spinal cord, thereby participating in morphine tolerance. This may provide new targets for the treatment of morphine tolerance.

01 Oct 2024·International Immunopharmacology

Oltipraz attenuated cerebral ischemia–reperfusion injury through inhibiting the oxidative stress and ferroptosis in mice

Article

Author: Zhu, Guohong ; Hu, Yang ; Jian, Wenting ; Jiang, Jingjing ; Ma, Huigai ; Xu, Jinfei ; Gong, Yuan ; Zhang, Qingyun

Oltipraz (OPZ) is a synthetic dithiolethione and is considered a novel activator of nuclear factor E2-related factor 2 (Nrf2). Increasing evidence indicates that Nrf2 protects against cerebral ischemia/reperfusion (I/R) injury by antagonizing ferroptosis and lipid peroxidation. However, the protective effects of OPZ on cerebral I/R injury remain to be elucidated. We investigated the in vitro and in vivo neuroprotective effects of OPZ. Mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) to construct an in vivo model and PC12 cells were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model. OPZ administration reduced the infarct volume and brain water content, and alleviated the neurological deficit of MCAO/R mice. Moreover, OPZ ameliorated MCAO/R-induced oxidative stress by decreasing the levels of 4-HNE and MDA and increasing the activities of SOD and GSH. We also found that OPZ ameliorated MCAO/R-induced ferroptosis by increasing SLC7A11 and GPX4 protein expression and downregulating ACSL4 protein expression. Similarly, the in vitro results revealed that OGD/R-induced oxidative stress and ferroptosis. Finally, mechanistic analysis revealed that OPZ significantly upregulated the Nrf2 expression and Nrf2 knockout (Nrf2 KO) abolished the OPZ-mediated protective effects. Taken together, these findings demonstrate that OPZ ameliorates cerebral I/R injury by suppressing the oxidative stress and ferroptosis.

01 Feb 2024·Naunyn-Schmiedeberg's Archives of Pharmacology

Efficacy of oltipraz in preventing acetaminophen-induced liver injury in mice

Article

Author: Mikami, Kenji ; Masubuchi, Yasuhiro

Oltipraz (OPZ) is a synthetic dithiolethione with potential as a cancer chemopreventive agent, which can work by inducing detoxification enzymes. OPZ is an activator of nuclear factor erythroid 2-related factor 2 (Nrf2), suggesting its involvement in enzyme induction and possible protection against drug-induced liver injury. In this study, we present OPZ-mediated protection of mice against acetaminophen (APAP)-induced liver injury and discuss its possible contributing factors. Overnight-fasted male CD-1 mice were administered APAP intraperitoneally, and some mice were administered OPZ 16 h before APAP. Hepatotoxicity was assessed by measuring serum alanine aminotransferase leakage and histopathological evaluation. The hepatic mRNA expressions of CYP2E1, glutamate cysteine ligase (GCL), and NAD(P)H:quinone oxidoreductase (NQO1) were measured by real-time reverse-transcription polymerase chain reaction. OPZ protected mice from APAP-induced liver injury in a dose-dependent manner, but did not alter hepatic glutathione (GSH) content or GCL expression in control mice, indicating that its hepatoprotective effect is not due to changes in basal GSH levels. OPZ did not affect CYP2E1 expression or APAP-induced early GSH depletion, suggesting it does not inhibit the metabolic activation of APAP to produce N-acetyl-p-benzoquinone imine. In contrast, after GSH depletion, OPZ accelerated hepatic GSH recovery. APAP significantly increased GCL expression during liver injury, but OPZ treatment only led to additional NQO1 expression. This suggests that NQO1 is responsible for the enhanced GSH recovery and protection against APAP-induced liver injury seen in OPZ-treated mice. In summary, OPZ protects against APAP-induced liver injury by inducing NQO1 expression and resulting in improved GSH recovery.

100 Deals associated with Oltipraz

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External Link

KEGG	Wiki	ATC	Drug Bank
-	Oltipraz	-	DB12539

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Nonalcoholic Steatohepatitis	Phase 2	-	Sanofi	-
Nonalcoholic Steatohepatitis	Phase 2	-	Pfizer Inc.	-
Nonalcoholic Steatohepatitis	Phase 2	-	Canopus Holding SA	-
Colonic Cancer	Preclinical	United States	University of Pennsylvania	01 Apr 2004
Liver Cirrhosis	Discovery	South Korea	Pharma King Co., Ltd.	01 Feb 2014
Metabolic dysfunction-associated steatotic liver disease	Discovery	South Korea	Pharma King Co., Ltd.	01 Feb 2014

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01373554 (Pubmed \| Aliment Pharmacol Ther)	Phase 2	Metabolic dysfunction-associated steatotic liver disease	60	Placebo	yjiobbszzf(fozdnpxnav) = uodketmgvl tcsqmicjbw (bzjbjvkvoc ) View more	-	01 Apr 2017
				Oltipraz 30 mg	yjiobbszzf(fozdnpxnav) = lrddfcftwn tcsqmicjbw (bzjbjvkvoc )