Delving into the Latest Updates on Dimebolin hydrochloride with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Dimebolin, Dimebon, Latrepirdine

+ [4]

Target

H1 receptor

Mechanism

H1 receptor antagonists(Histamine H1 receptor antagonists)

Therapeutic Areas

Immune System DiseasesInfectious DiseasesOtorhinolaryngologic Diseases+ [1]

Active Indication

HypersensitivityRhinitis, Allergic

Inactive Indication

Alzheimer DiseaseHuntington Diseaseliver function failure

Originator Organization-

Active Organization-

Inactive Organization

Pfizer Inc.MediVation, Inc.

Drug Highest PhaseApproved

First Approval Date

RU (01 Jan 1983),

HypersensitivityRhinitis, Allergic

RegulationOrphan Drug (US)

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Structure/Sequence

Molecular FormulaC21H27Cl2N3

InChIKeyGTWLIQOLGOZTLF-UHFFFAOYSA-N

CAS Registry97657-92-6

Background:Alzheimer's disease is a type of dementia that affects neuronal function, leading to a decline in cognitive functions. Serotonin-6 (5HT6) receptors are implicated in the etiology of neurological diseases. 5HT6 receptor antagonists act as anti-dementia agents. PDB ID: 7YS6 represents a membrane protein, and amplification and overexpression of this protein are associated with Alzheimer's disease. Coumarin-fused phenothiazines are significant anti-Alzheimer's agents due to their inhibitory activity on the Serotonin- 6 receptor.background:Alzheimer’s disease is a type of dementia, affecting neuronal function and leading to decline in cognitive functions. Serotonin-6 (5HT6) receptors are responsible for the etiology of neurological diseases. The 5HT6 receptor antagonists are acting as anti-dementia agents. PDB id: 7YS6 is a membrane protein. Amplification and over expression of this protein is connected to Alzheimer’s disease. Coumarin fused phenothiazines are consequential anti-Alzheimer’s agents because of their Serotonin-6 receptor inhibitory activity.Objectives:Numerous previously unreported Coumarin-substituted Phenothiazines [A2 to A50] were designed using in-silico methods to evaluate their 5HT6 receptor antagonistic activity. Molecular modeling techniques were employed to study the ligands [A2 to A50] in interaction with the Serotonin-6 receptor (PDB ID: 7YS6) using Schrödinger Suite 2019-4.Methods:Molecular modeling studies of the designed ligands [A2 to A50] were conducted using the Glide module. In-silico ADMET screening was performed using the QikProp module, and binding free energy calculations were carried out using the Prime MM-GBSA module within the Schrödinger Suite. The binding affinity of the designed ligands [A2 to A50] towards 5HT6 receptors was determined based on Glide scores. Subsequently, ligand A31 underwent a 100 ns molecular dynamics simulation using the Desmond module of Schrödinger Suite 2020-1, which is based in New York, NY.Results:The majority of the designed ligands exhibited strong hydrogen bonding interactions and hydrophobic associations with the serotonin-6 receptor, which hinder its activity. These ligands achieved remarkable Glide scores within the range of -4.2859 to -7.7128, in comparison to reference standards such as Idalopirdine (-7.78149), Intepirdine (-5.20103), Latrepirdine (-5.54853), and the co-crystallized ligand (-7.02889). In-silico ADMET properties for these ligands fell within the recommended values for drug-likeness. It is worth noting that the MM-GBSA binding free energy of the most potent inhibitor was positive, indicating a strong binding interaction. Additionally, the dynamic behavior of the protein (7YS6)-ligand (A31) complex was studied by subjecting ligand A31 to a 100 ns molecular dynamics simulation.result:Majority of the designed ligands had proclaimed good hydrogen bonding interconnection and hydrophobic associations to hamper serotonin-6. The ligands got remarkable glide scores in the range of -4.2859 to -7.7128 by comparing with the standards Idalopirdine (-7.78149), Intepirdine (-5.20103), Latrepirdine (-5.54853) and Co-crystallized ligand (-7.02889). The in-silico ADMET properties were within the recommended values for drug-likeness. MM-GBSA binding free energy of the most intense inhibitor is positive. The dynamic behaviour of the protein (7YS6)-ligand (A31) complex was studied by subjecting the ligand A31 to molecular dynamics simulation at 100 ns.Conclusion:The results of this study reveal strong evidence supporting the potential of coumarin- substituted phenothiazine derivatives as effective Serotonin-6 receptor antagonists. Ligands [A2 to A50], which exhibited noteworthy Glide scores, hold promise for significant anti- Alzheimer activity. Further in-vitro and in-vivo investigations are warranted to explore and confirm their therapeutic potential.

01 May 2023·Current Neuropharmacology

Mitochondrial Medicine: A Promising Therapeutic Option Against Various Neurodegenerative Disorders

Review

Author: Almikhlafi, Mohannad A. ; Alghamdi, Badrah S. ; Ashraf, Ghulam Md. ; Jana, Ankit ; Alqurashi, Thamer M. ; Karami, Mohammed M. ; Majrashi, Mohammed

Abstract:Abnormal mitochondrial morphology and metabolic dysfunction have been observed in many neurodegenerative disorders (NDDs). Mitochondrial dysfunction can be caused by aberrant mitochondrial DNA, mutant nuclear proteins that interact with mitochondria directly or indirectly, or for unknown reasons. Since mitochondria play a significant role in neurodegeneration, mitochondriatargeted therapies represent a prosperous direction for the development of novel drug compounds that can be used to treat NDDs. This review gives a brief description of how mitochondrial abnormalities lead to various NDDs such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. We further explore the promising therapeutic effectiveness of mitochondria- directed antioxidants, MitoQ, MitoVitE, MitoPBN, and dimebon. We have also discussed the possibility of mitochondrial gene therapy as a therapeutic option for these NDDs.

01 Jan 2023·Advances in protein chemistry and structural biology

Targeting mitochondrial dysfunction to salvage cellular senescence for managing neurodegeneration.

Article

Author: Sharma, Komal ; Sarkar, Joyobrata ; Ghosh, Rishika ; Dixit, Anubhuti ; Trisal, Anchal ; Singh, Abhishek Kumar

Aging is an inevitable phenomenon that causes a decline in bodily functions over time. One of the most important processes that play a role in aging is senescence. Senescence is characterized by accumulation of cells that are no longer functional but elude the apoptotic pathway. These cells secrete inflammatory molecules that comprise the senescence associated secretory phenotype (SASP). Several essential molecules such as p53, Rb, and p16INK4a regulate the senescence process. Mitochondrial regulation has been found to play an important role in senescence. Reactive oxygen species (ROS) generated from mitochondria can affect cellular senescence by inducing the persistent DNA damage response, thus stabilizing the senescence. Evidently, senescence plays a major contributory role to the development of age-related neurological disorders. In this chapter, we discuss the role of senescence in the progression and onset of several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Moreover, we also discuss the efficacy of certain molecules like MitoQ, SkQ1, and Latrepirdine that could be proven therapeutics with respect to these disorders by regulating mitochondrial activity.

100 Deals associated with Dimebolin hydrochloride

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External Link

KEGG	Wiki	ATC	Drug Bank
-	Dimebolin hydrochloride	R	DB11725

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Hypersensitivity	RU	-	01 Jan 1983
Rhinitis, Allergic	RU	-	01 Jan 1983

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Huntington Disease	Phase 2	GB	Pfizer Inc.	01 Jul 2009
Huntington Disease	Phase 2	DK	MediVation, Inc.	01 Jul 2009
Huntington Disease	Phase 2	CA	MediVation, Inc.	01 Jul 2009
Huntington Disease	Phase 2	DK	MediVation, Inc.	01 Jul 2009
Huntington Disease	Phase 2	DE	Pfizer Inc.	01 Jul 2009
Huntington Disease	Phase 2	GB	Pfizer Inc.	01 Jul 2009
Alzheimer Disease	Phase 2	US	MediVation, Inc.	01 May 2008
Huntington Disease	Phase 1	DE	Pfizer Inc.	01 Jul 2009
Huntington Disease	Phase 1	CA	MediVation, Inc.	01 Jul 2009
Alzheimer Disease	Phase 1	US	MediVation, Inc.	01 May 2008

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00975481 (CTgov)	Phase 1	Alzheimer Disease \| Huntington Disease	36	placebo (Placebo)	iakdsgjahr(wgmqwvqstw) = snhznebtpx eematawqwl (fdlaigsggd, kxqtwftdpa - zqbowbuxrk) View more	-	02 Apr 2013
				alprazolam (Alprazolam 1 mg)	iakdsgjahr(wgmqwvqstw) = ydmlafvsxt eematawqwl (fdlaigsggd, ozwwnmqduq - lrfocmmpsj) View more
NCT00920946 (Pubmed \| JAMA Neurol)	Phase 3	Huntington Disease	403	Latrepirdine 20 mg	qfxmaajfyf(tqfkdlaodg) = mcdigdjvfj dluastpbfx (fkmafkskuy )	Negative	01 Jan 2013
				Placebo	qfxmaajfyf(tqfkdlaodg) = atnyftwkyz dluastpbfx (fkmafkskuy )
NCT01066546 (CTgov)	Phase 3	Alzheimer Disease	5	Dimebon tablet for oral administration	rtziiszyrs(vvctcetofl) = zczjsjnoun zlmciapvlw (wcxtmpbmty, edbfsskxvm - gjwshytpts) View more	-	02 Oct 2012
NCT00912288 (CTgov)	Phase 3	Alzheimer Disease	86	Dimebon 20 mg po TID (Dimebon)	qtfkcdvicv(aethdlpusc) = kzmnyfxrzf ogyfvgjcmk (tclqdqkbfc, ggcqtvsiad - wlsvittxgw) View more	-	02 Oct 2012
				Placebo po TID (Placebo)	qtfkcdvicv(aethdlpusc) = vcgpwkpfnj ogyfvgjcmk (tclqdqkbfc, rdeiupanpj - dnwrxmtqwm) View more
NCT00497159 (Pubmed)	Phase 2	Huntington Disease	91	Latrepirdine 20 mg	(oxxndpeufm): treatment effect = 0.97 (95% CI, 0.1 - 1.85)	-	01 Feb 2010
				Placebo
AAIC2008	Not Applicable	Alzheimer Disease	183	Dimebon 20 mg	(clovmyzudw) = Dimebon was well-tolerated in both mild and moderate AD patients through one year, with dry mouth as the most common drug-related adverse event (%) reported ykcdgdpgof (tsdmmlptef )	Positive	01 Jul 2008
AAIC2007	Not Applicable	Alzheimer Disease	183	Dimebon 20 mg	(ybwuzqhlay) = jmgyfprjih sdndrptaub (qsqhaijlas ) View more	-	01 Jul 2007