Delving into the Latest Updates on Butoconazole Nitrate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

1-[4-(4-Chloro-phenyl)-2-(2,6-dichloro-phenylsulfanyl)-butyl]-1H-imidazole, Butoconazole nitrate (USP)

+ [5]

Target

fungal CYP51A1

Mechanism

fungal CYP51A1 inhibitors(Fungal CYP51A1 inhibitors)

Therapeutic Areas

Infectious DiseasesUrogenital Diseases

Active Indication

CandidiasisCandidiasis, Vulvovaginal

Inactive Indication-

Originator Organization

Bayer AG

Active Organization

Jinan Haitai Medical Technology Co., Ltd.AMAG Pharma USA, Inc.Jinan Hongruichuangbo Pharmaceutical Technology Development Co., Ltd.

Inactive Organization

Jiangsu Yangtze River Pharmaceutical Group Co., Ltd.

Bayer AG

Drug Highest PhaseApproved

First Approval Date

US (21 Dec 1995),

Candidiasis

Regulation-

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Structure

Molecular FormulaC19H18Cl3N3O3S

InChIKeyZHPWRQIPPNZNML-UHFFFAOYSA-N

CAS Registry64872-77-1

View All Structures (2)

The aryl hydrocarbon receptor (AhR) functions as a vital ligand-activated transcription factor, governing both physiological and pathophysiological processes. Notably, it responds to xenobiotics, leading to a diverse array of outcomes. In the context of drug repurposing, we present here a combined approach of utilizing structure-based virtual screening and molecular dynamics simulations. This approach aims to identify potential AhR modulators from Drugbank repository of clinically approved drugs. By focusing on the AhR PAS-B binding pocket, our screening protocol included binding affinities calculations, complex stability, and interactions within the binding site as a filtering method. Comprehensive evaluations of all DrugBank small molecule database revealed ten promising hits. This included flibanserin, butoconazole, luliconazole, naftifine, triclabendazole, rosiglitazone, empagliflozin, benperidol, nebivolol, and zucapsaicin. Each exhibiting diverse binding behaviors and remarkably very low binding free energy. Experimental studies further illuminated their modulation of AhR signaling, and showing that they are consistently reducing AhR activity, except for luliconazole, which intriguingly enhances the AhR activity. This work demonstrates the possibility of using computational modelling as a quick screening tool to predict new AhR modulators from extensive drug libraries. Importantly, these findings hold immense therapeutic potential for addressing AhR-associated disorders. Consequently, it offers compelling prospects for innovative interventions through drug repurposing.

01 Mar 2024·Liver International

The integrated stress response‐related expression of CHOP due to mitochondrial toxicity is a warning sign for DILI liability

Article

Author: van de Water, Bob ; Eakins, Julie ; de Jong, Brechtje ; Pellegrino‐Coppola, Damiano ; Vlasveld, Matthijs ; Walker, Paul ; Callegaro, Giulia ; Lok, Samantha ; van Oost, Siddh ; Wink, Steven ; Fisher, Ciarán ; Burger, Gerhard

AbstractBackground and AimsDrug‐induced liver injury (DILI) is one of the most frequent reasons for failure of drugs in clinical trials or market withdrawal. Early assessment of DILI risk remains a major challenge during drug development. Here, we present a mechanism‐based weight‐of‐evidence approach able to identify certain candidate compounds with DILI liabilities due to mitochondrial toxicity.MethodsA total of 1587 FDA‐approved drugs and 378 kinase inhibitors were screened for cellular stress response activation associated with DILI using an imaging‐based HepG2 BAC‐GFP reporter platform including the integrated stress response (CHOP), DNA damage response (P21) and oxidative stress response (SRXN1).ResultsIn total 389, 219 and 104 drugs were able to induce CHOP‐GFP, P21‐GFP and SRXN1‐GFP expression at 50 μM respectively. Concentration response analysis identified 154 FDA‐approved drugs as critical CHOP‐GFP inducers. Based on predicted and observed (pre‐)clinical DILI liabilities of these drugs, nine antimycotic drugs (e.g. butoconazole, miconazole, tioconazole) and 13 central nervous system (CNS) agents (e.g. duloxetine, fluoxetine) were selected for transcriptomic evaluation using whole‐genome RNA‐sequencing of primary human hepatocytes. Gene network analysis uncovered mitochondrial processes, NRF2 signalling and xenobiotic metabolism as most affected by the antimycotic drugs and CNS agents. Both the selected antimycotics and CNS agents caused impairment of mitochondrial oxygen consumption in both HepG2 and primary human hepatocytes.ConclusionsTogether, the results suggest that early pre‐clinical screening for CHOP expression could indicate liability of mitochondrial toxicity in the context of DILI, and, therefore, could serve as an important warning signal to consider during decision‐making in drug development.

11 Jan 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Design and Discovery of Novel NLRP3 Inhibitors and PET Imaging Radiotracers Based on a 1,2,3-Triazole-Bearing Scaffold

Q1 · MEDICINE

Article

Author: Liu, Yan ; Tanzi, Rudolph ; Xu, Yulong ; Kaur, Baljit ; Wang, Changning ; Biby, Savannah ; Zhang, Shijun ; Xu, Yiming ; Zhang, Can ; Bagdasarian, Frederick Andrew ; Wey, Hsiao-Ying

The NOD-like receptor (NLR) family pyrin-domain-containing 3 (NLRP3) inflammasome, an essential component of the innate immune system, has been emerging as a viable drug target and a potential biomarker for human diseases. In our efforts to develop novel small molecule NLRP3 inhibitors, a 1-(5-chloro-2-methoxybenzyl)-4-phenyl-1H-1,2,3-triazole scaffold was designed via a rational approach based on our previous leads. Structure-activity relationship studies and biophysical studies identified a new lead compound 8 as a potent (IC₅₀: 0.55 ± 0.16 μM), selective, and direct NLRP3 inhibitor. Positron emission tomography (PET) imaging studies of [¹¹C]8 demonstrated its rapid and high brain uptake as well as fast washout in mice and rhesus macaque. Notably, plasma kinetic analysis of this radiotracer from the PET/magnetic resonance imaging studies in rhesus macaque suggested radiometabolic stability. Collectively, our data not only encourage further studies of this lead compound but also warrant further optimization to generate additional novel NLRP3 inhibitors and suitable central nervous system PET radioligands with translational promise.

100 Deals associated with Butoconazole Nitrate

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External Link

KEGG	Wiki	ATC	Drug Bank
D00880	Butoconazole Nitrate	G01AF15	DB00639

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Candidiasis	CN	AMAG Pharma USA, Inc.	24 Jan 2009

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Candidiasis, Vulvovaginal	Preclinical	CN	Jiangsu Yangtze River Pharmaceutical Group Co., Ltd.	19 May 2013

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01039584 (CTgov)	Not Applicable	Candidiasis, Vulvovaginal	611	Butoconazole Nitrate Vaginal Cream (Test Product)	hnzmxvcmdd(vexkqmguts) = dpjsxghqwp kwesjnkjfj (vuhqbqiuth, ivkcviipcw - rfnfcblnif) View more	-	21 Jan 2013
				Gynazole 1 vaginal cream (Reference Product)	hnzmxvcmdd(vexkqmguts) = tdjojwjxaf kwesjnkjfj (vuhqbqiuth, ojvbbxbntq - qjmhemzfjr) View more