ET_A Antagonist

Ambrisentan is a selective ET type A receptor (ETAR) antagonist.

Macitentan (ACT-064992) is an orally active, non-peptide dual ETA and ETB (endothelin receptor) antagonist. Macitentan has the potential for idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH).

Aprocitentan (ACT-132577) is the major and pharmacologically active metabolite of Macitentan. Aprocitentan is an orally active dual ETA/ETB antagonist with IC₅₀s of 3.4 nM and 987 nM, and pA₂ valus of 6.7 and 5.5, respectively. Aprocitentan is an antihypertensive agent.

Sitaxsentan sodium (IPI 1040 sodium; TBC11251 sodium) is a potent, selective and orally active endothelin A receptor (ETA) antagonist with an IC₅₀ of 1.4 nM and a K_i of 0.43 nM. Sitaxsentan sodium exhibits an IC₅₀ for the ETB receptor of as high as 9800 nM. Sitaxsentan sodium is metabolized by CYP2C9 and CYP3A4, normalizes shunt-induced endothelial abnormalities, restores BMPR signaling, and suppresses pulmonary vascular remodeling and hemodynamic deterioration. Sitaxsentan sodium can be applied in the research of pulmonary arterial hypertension and portopulmonary hypertension.

PD151242 is a selective competitive antagonist of the endothelin ET_A receptor, with K_D values of 0.65 nM, 0.64 nM and 1.92 nM for human, rat and porcine receptors, respectively, and a K_D value of 104 μM for the human ET_β receptor. When radiolabeled as [¹²⁵I]-PD151242, PD151242 can be used to visualize and localize renal vascular ET_A receptors.

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.

BQ-123 is a potent and selective endothelin A (ETA) receptor antagonist with an IC₅₀ of 7.3 nM and a K_i of 25 nM. BQ-123 inhibits endothelin-1-mediated proliferation of human pulmonary artery smooth muscle cells and lowers blood pressure in different rat models of hypertension.

Sulfisoxazole (Sulfafurazole) is an orally active endothelin receptor antagonist with IC₅₀ values of 0.60 μM and 22 μM against endothelin receptor A and endothelin receptor B, respectively. Sulfisoxazole is a sulfonamide antibacterial agent with an oxazole substituent. Sulfisoxazole inhibits breast cancer exosome release by targeting endothelin receptor A.

Zibotentan (ZD4054) is a potent, selective and orally active endothelin A (ET_A) receptor antagonist with a K_i of 13 nM. Zibotentan has no inhibitory effect on ETB. Zibotentan has anticancer effects and can be used for castration-resistant prostate cancer (CRPC) research.

Tezosentan (RO 610612) is an endothelin (ET) receptor antagonist, with pA₂s of 9.5, 7.7 for ET_A and ET_B receptors, respectively.

IRL 2500 is a potent Endothelin receptor antagonist. IRL 2500 shows IC₅₀ values of 1.3 and 94 nM for ET_B and ET_A receptors, respectively. IRL 2500 inhibits ETB receptor-mediated blood pressure increase and renal vascular resistance in rats in vivo.

A-192621, a chemical probe, is a potent, nonpeptide, orally active and selective endothelin B (ET_B) receptor antagonist with an IC₅₀ of 4.5 nM and a K_i of 8.8 nM. The selectivity of A-192621 is 636-fold higher than ET_A (IC₅₀ of 4280 nM and K_i of 5600 nM). A-192621 promotes apoptosis in PASMCs. A-192621 alos causes elevation of arterial blood pressure and an elevation in the plasma ET-1 level.

Macitentan-d₄ is a deuterium labeled Sulfamethoxazole. Macitentan is an orally active, non-peptide dual ETA and ETB (endothelin) receptor antagonist. Macitentan has the potential for idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH).

Aprocitentan-d₄ is a deuterium labeled Aprocitentan. Aprocitentan is a major and pharmacologically active metabolite of Macitentan. Aprocitentan is an orally active dual ETA/ETB antagonist with IC50s of 3.4 nM and 987 nM, and pA2 valus of 6.7 and 5.5, respectively. Aprocitentan is an antihypertensive agent.

BMS 182874 is an orallyactive, highly selective endothelin receptor (ET_A receptor) antagonist, with IC₅₀ value of 0.150 μM, K_i of 0.055 μM. BMS 182874 reduces the arterial pressure of Deoxycorticosterone acetate (HY-B1472) induced hypertension model in rats, and can be used for cardiovascular disease research.

Ro 46-8443 is the first non-peptide endothelin ET_B receptor selective antagonist. Ro 46-8443 displays an at least 100-fold selectivity for ET_B (IC₅₀: 34-69 nM) over ET_A receptors (IC₅₀: 6800 nM).

Avosentan (Ro 67-0565; SPP-301) is an orally active endothelin (ETA) receptor antagonist. Avosentan can block the ETA receptor, thereby reducing vascular contraction and exerting a renal protective effect. Avosentan inhibits vascular contraction caused by ET-1 and alleviates the reduction in retinal and optic nerve head blood flow induced by it, lowering intraocular pressure in the glaucoma monkey model. Avosentan non-specifically blocks ETB receptors at high doses, inhibiting ETB-mediated diuresis and natriuresis, and may cause fluid retention. Avosentan can be used to reduce proteinuria with diabetic nephropathy, but induces significant fluid overload and congestive heart failure.

Nebentan (YM598 free base) is a potent, selective and orally active non-peptide endothelin ET_A receptor antagonist through the modification of Bosentan (HY-A0013). Nebentan inhibits [¹²⁵I] endothelin-1 binding to cloned human endothelin ETA and ETB receptor, with K_i of 0.697 nM and 569 nM, respectively. YM598 can ameliorate the progression of cor pulmonale and myocardial infarction in vivo.

Nebentan potassium (YM598) is a potent, selective and orally active non-peptide endothelin ET_A receptor antagonist through the modification of Bosentan (HY-A0013). Nebentan potassium inhibits [¹²⁵I] endothelin-1 binding to cloned human endothelin ETA and ETB receptor, with K_i of 0.697 nM and 569 nM, respectively. YM598 can ameliorate the progression of cor pulmonale and myocardial infarction in vivo.

J-104132 (L-753037) is a potent, orally active, selective and competitive ETA/ETB receptor antagonist with K_i of 0.034 nM for ETA and 0.104 nM for ETB receptors. J-104132 inhibits Endothelin-1 (ET-1) (HY-P71446)-induced signaling and vascular contractions in vitro. J-104132 alleviates hypertension, vascular remodeling, and diabetic endothelial dysfunction in vivo by dual ETA/ETB blockade. J-104132 can be used for research on diabetic vascular complications^[1][3].