Clemizole hydrochloride

IC50: 8 mM (NS4B)

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 bio-transformed 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 (https://clinicaltrials.gov/ct2/show/NCT00945880?term=Clemizole&rank=1).

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.

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.

Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment.[Pubmed:24002024]

Nat Commun. 2013;4:2410.

Dravet syndrome is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development and persistent drug-resistant seizures. One of its primary monogenic causes are mutations in Nav1.1 (SCN1A), a voltage-gated sodium channel. Here we characterize zebrafish Nav1.1 (scn1Lab) mutants originally identified in a chemical mutagenesis screen. Mutants exhibit spontaneous abnormal electrographic activity, hyperactivity and convulsive behaviours. Although scn1Lab expression is reduced, microarray analysis is remarkable for the small fraction of differentially expressed genes (~3%) and lack of compensatory expression changes in other scn subunits. Ketogenic diet, diazepam, valproate, potassium bromide and stiripentol attenuate mutant seizure activity; seven other antiepileptic drugs have no effect. A phenotype-based screen of 320 compounds identifies a US Food and Drug Administration-approved compound (clemizole) that inhibits convulsive behaviours and electrographic seizures. This approach represents a new direction in modelling pediatric epilepsy and could be used to identify novel therapeutics for any monogenic epilepsy disorder.

Pharmacological investigation into the effects of histamine and histamine analogues on guinea-pig and rat colon in vitro.[Pubmed:3742147]

Br J Pharmacol. 1986 Jul;88(3):501-6.

The effects of histamine and specific histamine agonists has been examined on isolated longitudinal colon strips of guinea-pig and rat. Histamine and 2-pyridyl-ethylamine but not 4 methylhistamine produced a concentration-related contractile response in the guinea-pig colon. The H1-antagonist clemizole antagonized competitively the effect of histamine but the H2-antagonist ranitidine did not modify the dose-response curve to histamine in the guinea-pig colon. Atropine, hexamethonium, prazosin and propranolol failed to modify the contractile response to histamine. Tone induced with KCl in guinea-pig isolated colon was not modified by histamine agonists even in tissues pretreated with clemizole or ranitidine. Histamine and histamine analogues were without effect on the isolated longitudinal strip of the rat colon. It is concluded that histamine produced dose-dependent contractions of the guinea-pig colon due to direct activation of H1-histamine receptors. There is no evidence in favour of the existence of H2-histamine receptors in this preparation. The lack of effect of histamine agonists in rat colon strip argues against the existence of histamine receptors in this preparation.

Clemizole hydrochloride 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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