ABT-546

Based on its outstanding (25,000-fold) selectivity for Endothelin A over Endothelin B and excellent selectivity against a panel of 71 GPCR kinases, A-546 is a pharmacologically highly useful tool to study ET1A biology both in vitro and in vivo. Its overall utility is expanded by the fact that it is highly bioavailable and has demonstrated pharmacological activity at relatively low (<10 mg/kg) doses in rats. The relatively potent activity in vitro and in vivo suggests that it has a wide pharmacologic window relative to the d-Opioid receptor (62% inhibition at 10 uM) and d-Opioid receptor and the Cl- ionophore (61% inhibition at 10 uM). In a DiscoverX kinase binding assay panel, A-546 showed strong binding of PRKCH (100% @ 1 uM) and moderate binding against CDKL2 (61% @ 1 uM). This inhibition has not been assessed or reported in orthogonal assays, thus it unclear if it is pharmacologically relevant. Overall, these data support the use of A-546 in vitro and in vivo as a probe for Endothelin A biology and suggest that it is the best available ET1A antagonist probe available.