Clemizole

An H1 histamine receptor antagonist that substantially inhibits HCV replication by suppression of NS4B's RNA binding (IC50=24 nM) with little toxicity for the host cells; also selectively and efficiently blocks TRPC5 currents and Ca(2+) entry with IC50 of 1-1.3 uM, 6-fold selectivity over TRPC4β (IC50 = 6.4 μM), and almost 10-fold selectivity over TRPC3 (IC50 =9.1 uM) and TRPC6 (IC50=11.3 uM), only very weakly affects TRPM3, TRPM8 and TRPV1, V2, V3, and V4 channels. HCV Infection Phase 2 Clinical(In Vitro):Clemizole hydrochloride is found to inhibit HCV RNA replication in cell culture that is mediated by its suppression of NS4B’s RNA binding, with little toxicity for the host cell. The EC50 of Clemizole on the W55R mutant J6/JFH RNA is ~18 μM (2.25 times the EC50 of the wild-type RNA). Clemizole is a novel inhibitor of TRPC5 channels. Clemizole efficiently blocks TRPC5 currents and Ca2+ entry in the low micromolar range (IC50=1.0-1.3 μM). Clemizole exhibits a six-fold selectivity for TRPC5 over TRPC4β (IC50=6.4 μM), the closest structural relative of TRPC5, and an almost 10-fold selectivity over TRPC3 (IC50=9.1 μM) and TRPC6 (IC50=11.3 μM). Clemizole hydrochloride as a novel blocker of TRPC5 with a half-maximal inhibitory concentration of 1.1 μM. The concentration-response curves confirmed a concentration-dependent block of TRPC5 by Clemizole and revealed an apparent IC50 of 1.1±0.04 μM.(In Vivo):Clemizole hydrochloride has an unexpectedly short plasma half-life (measured at 0.15 hours); it is very rapidly biotransformed into a glucuronide (M14) and a dealkylated metabolite (M12) and into a variety of lesser metabolites in C57BL/6J mice.