Pyrrolimidazole, also known as 1-[(4-chlorophenyl)methyl]-2-(pyrrolidone-1-ylmethyl)benzimidazole or crimetazole, has antihistamine activity, moderate sedative effect, and significant antipruritic effect. Recent studies have shown that it has anti-hepatitis C virus activity. This product can prolong the effective refractory period of atrial myocardium and has been reported to treat atrial flutter.
ChEBI: A member of the class of benzimidazoles that is 1H-benzimidazole substituted by a pyrrolidin-1-ylmethyl and a 4-chlorobenzyl groups at positions 2 and 1 respectively.
From 13.1 g of N-p-chlorobenzyl-2-nitroaniline (MP 110°C, obtained in the
form of orange-red needles, from o-nitrochlorobenzene and pchlorobenzylamine by reaction for 3 hours at 150°C) by reduction with Raneynickel and hydrogen, in which reaction the substance may be suspended in
methanol or dissolved in methanol-ethyl acetate at normal pressure and at
about 40°C with combination of the theoretical quantity of hydrogen, 12.2 g
are obtained of o-amino-N-p-chlorobenzylaniline, which after recrystallization
from aqueous methanol has a MP of 90°C.
8 g of o-amino-N-p-chlorobenzylaniline and 2.8 g of pyridine are dissolved in
dry ether and reacted with an ethereal solution of 3.9 g of chloracetyl chloride
with cooling in a mixture of ice and common salt. 8 g of N-p-chlorobenzyl-N'-
chloracetyl-o-phenylene diamine are obtained which can be worked up in the
form of the crude product and, in the slightly colored form, has a MP of
130°C.
7.6 g of this compound are boiled with 3.9 g of pyrrolidine in 70 cc of toluene
for some hours under reflux. After extraction by shaking with water and
treatment with hydrochloric acid the hydrochloride is produced of N-pchlorobenzyl-N'-pyrrolidylacetyl-o-phenylene diamine together with some 1-pchlorobenzyl-2-N-pyrrolidylmethyl-benzimidazole. The former, after
recrystallization from butanol, melts with foaming at 205°C, the latter, after
recrystallization from butanol melts at 239°C to 241°C, and is in the form of
white microscopic rods. Boiling in nitrobenzene converts the former compound
into the latter.
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.
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].
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].
[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.
