Modulation of Kv 11.1 (hERG) channels by 5-(((1H-indazol-5-yl)oxy)methyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (ITP-2), a novel small molecule activator

British Journal of Pharmacology
Harinath SaleManjunath Ramarao

Abstract

Activators of Kv 11.1 (hERG) channels have potential utility in the treatment of acquired and congenital long QT (LQT) syndrome. Here, we describe a new hERG channel activator, 5-(((1H-indazol-5-yl)oxy)methyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (ITP-2), with a chemical structure distinct from previously reported compounds. Conventional electrophysiological methods were used to assess the effects of ITP-2 on hERG1a and hERG1a/1b channels expressed heterologously in HEK-293 cells. ITP-2 selectively increased test pulse currents (EC50 1.0 μM) and decreased tail currents. ITP-2 activated hERG1a homomeric channels primarily by causing large depolarizing shifts in the midpoint of voltage-dependent inactivation and hyperpolarizing shifts in the voltage-dependence of activation. In addition, ITP-2 slowed rates of inactivation and made recovery from inactivation faster. hERG1a/1b heteromeric channels showed reduced sensitivity to ITP-2 and their inactivation properties were differentially modulated. Effects on midpoint of voltage-dependent inactivation and rates of inactivation were less pronounced for hERG1a/1b channels. Effects on voltage-dependent activation and activation kinetics were not different from hERG1a channels...Continue Reading

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Citations

Sep 10, 2017·British Journal of Pharmacology·John S Mitcheson, Jules C Hancox
Oct 20, 2019·Cardiovascular Research·Matthew D PerryJamie I Vandenberg
Dec 3, 2020·European Journal of Medicinal Chemistry·Jacobus P D van VeldhovenAdriaan P IJzerman

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