Clemizole

The NS4B protein is a key player in HCV replication. Disrupting NS4B function thus represents an attractive new anti-HCV strategy. Combining clemizole with other anti-HCV agents could increase the antiviral effect achieved with 1 active drug alone and decrease emergence of viral resistance.

In vitro: Although significant, clemizole’s antiviral effect was moderate (50% effective concentration of 8 mM against a HCV genotype 2a clone). Clemizole’s antiviral effect was highly synergistic with the HCV protease inhibitors VX950 and SCH503034, without toxicity. In contrast, clemizole combinations with either interferon, ribavirin, or the nucleoside (NM283) and nonnucleoside (HCV796) HCV polymerase inhibitors were additive [1].

In vivo: Clemizole had an unexpectedly short plasma half-life; it was very rapidly biotransformed into a glucuronide (M14) and a dealkylated metabolite (M12) and into a variety of lesser metabolites in C57BL/6J mice [2].

Clinical trial: The purpose of a study was to test the hypothesis that clemizole hydrochloride was safe and well tolerated when administered to subjects who were infected with hepatitis C virus and had not yet received treatment. This clinical study would also examine how the virus and body respond to clemizole hydrochloride.

References:
[1] Einav S, Sobol HD, Gehrig E, Glenn JS.  The hepatitis C virus (HCV) NS4B RNA binding inhibitor clemizole is highly synergistic with HCV protease inhibitors. J Infect Dis. 2010;202(1):65-74.
[2] Nishimura T, Hu Y, Wu M, Pham E, Suemizu H, Elazar M, Liu M, Idilman R, Yurdaydin C, Angus P, Stedman C, Murphy B, Glenn J, Nakamura M, Nomura T, Chen Y, Zheng M, Fitch WL, Peltz G.  Using chimeric mice with humanized livers to predict human drug metabolism and a drug-drug interaction. J Pharmacol Exp Ther. 2013;344(2):388-96. doi: 10.1124/jpet.112.198697. Epub 2012 Nov 8.

Selective inhibition of heme oxygenase-2 activity by analogs of 1-(4-chlorobenzyl)-2-(pyrrolidin-1-ylmethyl)-1H-benzimidazole (clemizole): Exploration of the effects of substituents at the N-1 position.[Pubmed:24021581]

Bioorg Med Chem. 2013 Nov 1;21(21):6788-95.

Several analogs based on the lead structure of 1-(4-chlorobenzyl)-2-(pyrrolidin-1-ylmethyl)-1H-benzimidazole (Clemizole) were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). Many of the compounds were found to be potent and highly selective for the HO-2 isozyme (constitutive), and had substantially less inhibitory activity on the HO-1 isozyme (inducible). The compounds represent the first report of highly potent and selective inhibitors of HO-2 activity, and complement our suite of selective HO-1 inhibitors. The study has revealed many candidates based on the inhibition of heme oxygenases for potentially useful pharmacological and therapeutic applications.

Clemizole hydrochloride is a novel and potent inhibitor of transient receptor potential channel TRPC5.[Pubmed:25140002]

Mol Pharmacol. 2014 Nov;86(5):514-21.

Canonical transient receptor potential channel 5 (TRPC5) is a nonselective, Ca(2+)-permeable cation channel that belongs to the large family of transient receptor potential channels. It is predominantly found in the central nervous system with a high expression density in the hippocampus, the amygdala, and the frontal cortex. Several studies confirm that TRPC5 channels are implicated in the regulation of neurite length and growth cone morphology. We identified Clemizole as a novel inhibitor of TRPC5 channels. Clemizole efficiently blocks TRPC5 currents and Ca(2+) entry in the low micromolar range (IC50 = 1.0-1.3 microM), as determined by fluorometric intracellular free Ca(2+) concentration ([Ca(2+)]i) measurements and patch-clamp recordings. Clemizole blocks TRPC5 currents irrespectively of the mode of activation, for example, stimulation of G protein-coupled receptors, hypo-osmotic buffer conditions, or by the direct activator riluzole. Electrophysiological whole-cell recordings revealed that the block was mostly reversible. Moreover, Clemizole was still effective in blocking TRPC5 single channels in excised inside-out membrane patches, hinting to a direct block of TRPC5 by Clemizole. Based on fluorometric [Ca(2+)]i measurements, Clemizole exhibits a sixfold selectivity for TRPC5 over TRPC4beta (IC50 = 6.4 microM), the closest structural relative of TRPC5, and an almost 10-fold selectivity over TRPC3 (IC50 = 9.1 microM) and TRPC6 (IC50 = 11.3 microM). TRPM3 and M8 as well as TRPV1, V2, V3, and V4 channels were only weakly affected by markedly higher Clemizole concentrations. Clemizole was not only effective in blocking heterologously expressed TRPC5 homomers but also TRPC1:TRPC5 heteromers as well as native TRPC5-like currents in the U-87 glioblastoma cell line.

Clemizole hydrochloride blocks cardiac potassium currents stably expressed in HEK 293 cells.[Pubmed:27886373]

Br J Pharmacol. 2017 Feb;174(3):254-266.

BACKGROUND AND PURPOSE: Clemizole, a histamine H1 receptor antagonist has a potential therapeutic effect on hepatitis C infection and also potently inhibits TRPC5 ion channels. The aim of the present study was to investigate whether Clemizole blocks cardiac K(+) currents and thus affects cardiac repolarization. EXPERIMENTAL APPROACH: Whole-cell patch techniques was used to examine the effects of Clemizole on hERG channel current, IKs and Kv 1.5 channel current in HEK 293 cell expression systems as well as on ventricular action potentials of guinea pig hearts. Isolated hearts from guinea pigs were used to determine the effect on the ECG. KEY RESULTS: Clemizole decreased hERG current by blocking both open and closed states of the channel in a concentration-dependent manner (IC50 : 0.07 muM). The S631A, S636A, Y652A and F656V hERG mutant channels reduced the inhibitory effect of Clemizole (IC50 : 0.82, 0.89, 1.49 and 2.98 muM, respectively), suggesting that Clemizole is a pore blocker of hERG channels. Clemizole also moderately decreased IKs and human Kv 1.5 channel current. Moreover, Clemizole increased the duration of the ventricular action potential in guinea pig hearts and the QTc interval in isolated perfused hearts from guinea pigs, in a concentration-dependent manner (0.1-1.0 muM). CONCLUSION AND IMPLICATIONS: Our results provide the first evidence that Clemizole potently blocks hERG channels, moderately inhibits cardiac IKs , delays cardiac repolarization and thereby prolongs QT interval. Thus, caution should be taken when Clemizole is used as a TRPC5 channel blocker or for treating hepatitis C infection.

Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome.[Pubmed:28073790]

Brain. 2017 Mar 1;140(3):669-683.

Dravet syndrome is a catastrophic childhood epilepsy with early-onset seizures, delayed language and motor development, sleep disturbances, anxiety-like behaviour, severe cognitive deficit and an increased risk of fatality. It is primarily caused by de novo mutations of the SCN1A gene encoding a neuronal voltage-activated sodium channel. Zebrafish with a mutation in the SCN1A homologue recapitulate spontaneous seizure activity and mimic the convulsive behavioural movements observed in Dravet syndrome. Here, we show that phenotypic screening of drug libraries in zebrafish scn1 mutants rapidly and successfully identifies new therapeutics. We demonstrate that Clemizole binds to serotonin receptors and its antiepileptic activity can be mimicked by drugs acting on serotonin signalling pathways e.g. trazodone and lorcaserin. Coincident with these zebrafish findings, we treated five medically intractable Dravet syndrome patients with a clinically-approved serotonin receptor agonist (lorcaserin, Belviq(R)) and observed some promising results in terms of reductions in seizure frequency and/or severity. Our findings demonstrate a rapid path from preclinical discovery in zebrafish, through target identification, to potential clinical treatments for Dravet syndrome.

Clemizole is an H1 histamine receptor antagonist, is found to substantially inhibit HCV replication. The IC50 of Clemizole for RNA binding by NS4B is 24±1 nM, whereas its EC50 for viral replication is 8 µM.

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