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

Action

antagonists

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.

License Organization-

Drug Highest PhaseApproved

First Approval Date

Russia (01 Jan 1983),

HypersensitivityRhinitis, Allergic

RegulationOrphan Drug (United States)

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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.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 MMGBSA 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.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. ; Alqurashi, Thamer M. ; Karami, Mohammed M. ; Jana, Ankit ; 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 Feb 2023·European Journal of Medicinal Chemistry

Wiskostatin and other carbazole scaffolds as off target inhibitors of dynamin I GTPase activity and endocytosis

Article

Author: Young, Kelly A ; Hamilton, Michael P ; Russell, Cecilia C ; Cardoso, David ; Robinson, Phillip J ; Chau, Ngoc ; Mathwin, Daniel ; McCluskey, Adam ; Baker, Jennifer R ; Cossar, Peter J ; Chiew, Beatrice

Wiskostatin (1-(3,6-dibromo-9H-carbazol-9-yl)-3-(dimethylamino)propan-2-ol) (1) is a carbazole-based compound reported as a specific and relatively potent inhibitor of the N-WASP actin remodelling complex (S-isomer EC₅₀ = 4.35 μM; R-isomer EC₅₀ = 3.44 μM). An NMR solution structure showed that wiskostatin interacts with a cleft in the regulatory GTPase binding domain of N-WASP. However, numerous studies have reported wiskostatin's actions on membrane transport and cytokinesis that are independent of the N-WASP-Arp2/3 complex pathway, but offer limited alternative explanation. The large GTPase, dynamin has established functional roles in these pathways. This study reveals that wiskostatin and its analogues, as well as other carbazole-based compounds, are inhibitors of helical dynamin GTPase activity and endocytosis. We characterise the effects of wiskostatin on in vitro dynamin GTPase activity, in-cell endocytosis, and determine the importance of wiskostatin functional groups on these activities through design and synthesis of libraries of wiskostatin analogues. We also examine whether other carbazole-based scaffolds frequently used in research or the clinic also modulate dynamin and endocytosis. Understanding off-targets for compounds used as research tools is important to be able to confidently interpret their action on biological systems, particularly when the target and off-targets affect overlapping mechanisms (e.g. cytokinesis and endocytosis). Herein we demonstrate that wiskostatin is a dynamin inhibitor (IC₅₀ 20.7 ± 1.2 μM) and a potent inhibitor of clathrin mediated endocytosis (IC₅₀ = 6.9 ± 0.3 μM). Synthesis of wiskostatin analogues gave rise to 1-(9H-carbazol-9-yl)-3-((4-methylbenzyl)amino)propan-2-ol (35) and 1-(9H-carbazol-9-yl)-3-((4-chlorobenzyl)amino)propan-2-ol (43) as potent dynamin inhibitors (IC₅₀ = 1.0 ± 0.2 μM), and (S)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-(dimethylamino)propan-2-ol (8a) and (R)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-(dimethylamino)propan-2-ol (8b) that are amongst the most potent inhibitors of clathrin mediated endocytosis yet reported (IC₅₀ = 2.3 ± 3.3 and 2.1 ± 1.7 μM, respectively).

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	Russia	-	01 Jan 1983
Rhinitis, Allergic	Russia	-	01 Jan 1983

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Huntington Disease	Phase 1	United Kingdom	Pfizer Inc.	01 Jul 2009
Huntington Disease	Phase 1	Canada	MediVation, Inc.	01 Jul 2009
Huntington Disease	Phase 1	Denmark	MediVation, Inc.	01 Jul 2009
Huntington Disease	Phase 1	Sweden	MediVation, Inc.	01 Jul 2009
Alzheimer Disease	Phase 1	United States	MediVation, Inc.	01 May 2008
Huntington Disease	Preclinical	Denmark	MediVation, Inc.	01 Jul 2009
Huntington Disease	Preclinical	Sweden	MediVation, Inc.	01 Jul 2009
Huntington Disease	Preclinical	United Kingdom	Pfizer Inc.	01 Jul 2009
Huntington Disease	Preclinical	Canada	MediVation, Inc.	01 Jul 2009
Alzheimer Disease	Preclinical	United States	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)	xhxowrunhm(lgkjxfqnob) = mgwrodtwbc kzrhhxtdic (tyizhjzspw, qdtjryrzpu - jgaugogvyg) View more	-	02 Apr 2013
				alprazolam (Alprazolam 1 mg)	xhxowrunhm(lgkjxfqnob) = pxpeexsaii kzrhhxtdic (tyizhjzspw, erotixozlp - zczmvbdunb) View more
NCT00920946 (Pubmed \| JAMA Neurol)	Phase 3	Huntington Disease	403	Latrepirdine 20 mg	ilaqwuxylu(smqykxpvvo) = rewfvzpmlk emvhpzdjnj (xqopwsardb )	Negative	01 Jan 2013
				Placebo	ilaqwuxylu(smqykxpvvo) = mjqydqxkjy emvhpzdjnj (xqopwsardb )
NCT01066546 (CTgov)	Phase 3	Alzheimer Disease	5	Dimebon tablet for oral administration	lxbmljuzmk(vnxaahylrd) = azxkrmyekp lqkhdsdgfj (bkhsgidkuf, itjslpiovh - oarjjbxyfj) View more	-	02 Oct 2012
NCT00912288 (CTgov)	Phase 3	Alzheimer Disease	86	Dimebon 20 mg po TID (Dimebon)	rcfubryxuh(tuhkgsaobj) = fnenyhephn lousmsvxdw (bhsspdygzl, hoqnlxcfqa - qucajbktae) View more	-	02 Oct 2012
				Placebo po TID (Placebo)	rcfubryxuh(tuhkgsaobj) = fmomcjfhst lousmsvxdw (bhsspdygzl, scbplujndy - ignmewddxi) View more
NCT00497159 (Pubmed)	Phase 2	Huntington Disease	91	Latrepirdine 20 mg	(nckljjuwtc): treatment effect = 0.97 (95% CI, 0.1 - 1.85)	-	01 Feb 2010
				Placebo
AAIC2008	Not Applicable	Alzheimer Disease	183	Dimebon 20 mg	(defidazbpp) = 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 rwcpssfhoq (pjlhpfquzf )	Positive	01 Jul 2008
AAIC2007	Not Applicable	Alzheimer Disease	183	Dimebon 20 mg	(kkiwnafqhm) = nqzaywopva vjvcsnasdi (zsksfmetkq ) View more	-	01 Jul 2007