Delving into the Latest Updates on Norketotifen with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

NKT, Nor-ketotifen

Target

H1 receptor

Mechanism

H1 receptor antagonists(Histamine H1 receptor antagonists)

Therapeutic Areas

Immune System DiseasesInfectious DiseasesOtorhinolaryngologic Diseases+ [2]

Active Indication-

Inactive Indication

Influenza, HumanInfluenza-like symptomsRhinitis, Allergic

Originator Organization

Emergo Therapeutics, Inc.Startup

Active Organization-

Inactive Organization

Emergo Therapeutics, Inc.Startup

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

Login to view timeline

Structure

Molecular FormulaC18H17NOS

InChIKeyIYSYPCSSDZBWHN-UHFFFAOYSA-N

CAS Registry34580-20-6

OBJECTIVETo explore the effect of nootkatone (NKT) on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and the mechanism underlying NKT improving the depressive-like behaviors.METHODSThe CUMS-induced depression model was established in mice. Fifty mice were randomized into 5 groups (n=10) in accordance with a random number table: control group, CUMS group, CUMS + NKT (6 mg/kg) group, CUMS + NKT (12 mg/kg) group, and CUMS + ketamine group. From the 22th day, NKT (6 or 12 mg/kg) or ketamine (0.5 mg/kg) was given with intragastric administration every day for 21 days. Behavioral tests including forced swimming test (FST), tail suspension test (TST), sucrose preference test (SPT) and open-field test (OFT) were carried out. The mRNA and protein expressions of interleukin (IL)-1β, IL-18, IL-6, and tumor necrosis factor (TNF)-α in hippocampus were assessed using quantitative realtime polymerase chain reaction (PCR), Western blot analysis, and enzyme linked immunosorbent assay. The nuclear factor-κB (NF-κB)/NOD-like receptor 3 (NLRP3) inflammasome pathway was analyzed using Western blot and immunofluorescence analysis.RESULTSNKT treatment improved CUMS-induced depressive-like behaviors in mice (P<0.05 or P<0.01). NKT significantly decreased the mRNA and protein levels of IL-1β, IL-18, IL-6, and TNF-α in hippocampus of CUMS mice (P<0.05 or P<0.01). Furthermore, NKT repressed CUMS-induced activation of NF-κB signaling and NLRP3 inflammasome (P<0.01). More important, Nigericin, a NLRP3 activator, destroyed the effect of NKT on repressing neuroinflammation and improving depressive-like behaviors (P<0.05 or P<0.01).CONCLUSIONNKT ameliorates the depressive-like symptoms, in part by repressing NF-κB/NLRP3-mediated neuroinflammation.

01 Nov 2022·Phytotherapy Research

Nootkatone alleviates rotenone‐induced Parkinson's disease symptoms through activation of the PI3K/Akt signaling pathway

Article

Author: Wan, Guohui ; Li, Qiuyu ; Yang, Xue ; Wei, Xiaojia ; Shi, Jinli ; Wang, Xiaomei ; Bian, Lihua ; Wang, Yuqing ; Yao, Ziwei ; Guo, Jianyou ; Li, Jiayuan

AbstractParkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Nootkatone (NKT) has been shown to have neuroprotective, anti‐inflammatory, and antioxidant effects and in this study, we systematically studied the efficacy and mechanism of action of NKT in rotenone (ROT)‐induced PD rats. Firstly, through behavioral experiments and brain tissue staining, we found that NKT alleviated behavioral dysfunction and protected dopaminergic neurons associated with ROT‐induced PD rats. Next, target prediction, protein–protein interaction (PPI), Gene Ontology (GO), and pathway enrichment analyses were used to obtain potential targets, specific biological processes, and molecular mechanisms of NKT for the potential treatment of PD. Furthermore, we also applied molecular docking to predict the binding capacity of NKT and related targets. Additionally, in vivo experiments confirmed that NKT could inhibit the expression of Mitogen‐activated protein kinase 3 (MAPK3) by activating the PI3K/Akt signaling pathway, reducing neuroinflammation, and ultimately ameliorating ROT‐induced PD symptoms. Taken together, the results of the study provide a clear explanation for the remission of PD symptoms by NKT, suggesting that it may be a promising candidate for the treatment of PD.

01 Apr 2022·Drug Development ResearchQ3 · MEDICINE

Ketotifen is a Prodrug. Norketotifen is the active metabolite.

Q3 · MEDICINE

Article

Author: Walle, Thomas ; Ciofalo, Vincent B. ; Arulnesan, Nada ; Pucaj, Kresimir ; Walle, Kristina ; Aberg, Axel Karl Gunnar ; Bolger, Gordon T.

ABSTRACTEvaluation of the in vitro human liver microsome and hepatocyte metabolism of ketotifen demonstrated that norketotifen (NK) is the major demethylated hepatic metabolite of ketotifen. It is here reported that NK is completely devoid of the severe and dose‐limiting sedative effects of ketotifen. Thus, while ketotifen is clinically dose‐limited to 1 mg, bid, there are no dose‐limiting sedative effects elicited by NK, even after the highest single‐dose (16 mg) or after repeat‐doses (8 mg × 7 days) in humans or after the highest doses given to dogs in repeat‐dose toxicological studies (40 mg/kg × 14 days). In addition, NK—but not ketotifen—was found to express potent and dose‐dependent inhibition of the release of the pro‐inflammatory cytokine TNFα from activated human buffy coat preparations. Thus, when used as an anti‐inflammatory drug, ketotifen is the sedating prodrug which is converted to NK a nonsedating metabolite with anti‐inflammatory activity.

100 Deals associated with Norketotifen

Login to view more data

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Influenza, Human	Phase 2	US	Emergo Therapeutics, Inc.Startup	21 Oct 2019
Influenza-like symptoms	Phase 2	US	Emergo Therapeutics, Inc.Startup	21 Oct 2019
Rhinitis, Allergic	Phase 2	US	Emergo Therapeutics, Inc.Startup	01 Apr 2019