ABT-546 (hydrochloride)

ABT-546 (A-216546) hydrochloride is an orally active ET_A receptor antagonist, with K_i values of 0.46 nM and 13000 nM for human ET_A and ET_B receptors, respectively, and exhibits >25000-fold selectivity over the ET_B receptor. ABT-546 hydrochloride effectively inhibits ET-1 (HY-P0202)-induced phosphoinositide hydrolysis (IC₅₀ = 0.59 nM) and arachidonic acid release (IC₅₀ = 3.03 nM), and antagonizes ET-1-induced contraction in isolated vascular rings. ABT-546 hydrochloride crosses the placental barrier but shows extremely low fetal exposure, with a favorable safety profile. ABT-546 hydrochloride inhibits ET-1-induced pressor response and downregulates the NLRP3/ROS/GSDMD-mediated pyroptosis pathway. ABT-546 hydrochloride can be used for research on abdominal aortic aneurysm^{[1][2][3][4][5][6]}. In Vitro:ABT-546 hydrochloride exhibits an IC₅₀ of 0.17-0.49 nM for the human ET_A receptor and 0.22-0.56 nM for the rat ET_A receptor in competitive binding assays; for the human ET_B receptor, its IC₅₀ is > 15000 nM, and for the porcine ET_B receptor, > 16000 nM, showing a selectivity of over 25000-fold^[1][2].
ABT-546 hydrochloride shows a K_i of 0.46 nM for the human ET_A receptor and a K_i of 13000 nM for the human ET_B receptor^[1][2].
ABT-546 (15-30 min) hydrochloride effectively inhibits ET-1-stimulated phosphoinositide (PI) hydrolysis in rat MMQ cells (IC₅₀ = 0.59 nM) and ET-1-stimulated arachidonic acid (AA) release in human pericardial smooth muscle cells (IC₅₀ = 3.03 nM), and it displays no agonist activity by itself^[1][2].
ABT-546 (10 μM) hydrochloride shows 98% inhibition of the ET_A receptor, 56% inhibition of the ET_B receptor, 62% inhibition of the δ-opioid receptor, and 61% inhibition of the Cl^- ion carrier in a receptor binding profile screening against 73 targets; no significant activity is observed for the remaining targets in the assay^[2].
ABT-546 hydrochloride antagonizes ET-1-induced vasoconstriction (ET_A-mediated) in isolated rat aortic rings with a pA₂ of 8.29, and it antagonizes Sarafotoxin 6c-induced vasoconstriction (ET_B-mediated) in isolated rabbit pulmonary artery rings with a pA₂ of 4.57, demonstrating its ET_A selectivity^[4].
ABT-546 (0.1-10 μM; 20-30 min) hydrochloride concentration-dependently and completely blocks ET-1-stimulated 2-deoxyglucose uptake in 3T3-L1 adipocytes and simultaneously inhibits ET-1-induced GLUT4 translocation^[5]. In Vivo:ABT-546 (1-100 mg/kg; oral; single administration) hydrochloride dose-dependently inhibits the ET-1 pressor response in normotensive rats, with an ED₅₀ value of 10 mg/kg, and its effect lasts for at least 8 hours; at 10 and 30 mg/kg, it does not affect the ET-1 depressor response, and only at 100 mg/kg does it show slight inhibition^[2][4].
ABT-546 (20 mg/kg/day; subcutaneous osmotic pump administration; on gestation days 14-21, for 7 days) hydrochloride crosses the placental barrier in pregnant rats but shows extremely low fetal exposure, produces no adverse effects on pregnancy outcomes or on offspring survival and growth, and improves offspring blood oxygen saturation on postnatal day 7^[3].
ABT-546 (20 mg/kg; intragastric administration; once daily) hydrochloride significantly reduces abdominal aortic diameter in the Ang II (HY-13948)/Bap (HY-107377)-induced abdominal aortic aneurysm model in C57BL/6 mice, downregulates NLRP3 inflammasome and ROS levels, and significantly decreases the release of activated GSDMD and the inflammatory cytokines IL-1β and IL-18^[6].