Ki: 61 nM for ETA in VSM-A10 cells; 48 nM for ETA in CHO cells
Endothelin (ET) was originally identified as a potent vasoactive substance secreted by endothelial cells that stimulated force development in isolated pig coronary arteries. ET-1 belongs to a family of highly conserved 21-amino-acid peptides produced in numerous tissues including the lung, kidney, eye, gut and central nervous system. BMS-182874 is a low molecular weight, nonpeptide endothelin (El) receptor antagonist.
In vitro: BMS-182874 competitively inhibited the binding of [125I]ET-1 to ETA receptors in rat vascular smooth muscle A10 (VSM-A10) cell membranes (Ki = 61 nM) and in CHO cells stably expressing the human ETA receptor (Ki = 48 nM), but was a weak inhibitor at ETB receptors (Ki > 50 μM) and non-ET receptors. BMS-l 82874 inhibited ET-l -stimulated inositol phosphate accumulation (KB 75 nM) and calcium mobilization (Ki = 140 nM) without suppressing the maximal responses in VSM-A10 cells [1].
In vivo: When administered either orally (ED50 = 30 μmol/kg) or intravenously (ED50 = 24 μmol/kg) to conscious, normotensive rats, BMS-182874 blunted the pressor response to exogenous ET-l . These data demonstrate that BMS-l 82874 is a competitive, selective and orally active ETA receptor antagonist [1].
Clinical trial: Up to now, BMS 182874 hydrochloride is still in the preclinical development stage.
Reference:
[1] MARIA L WEBB, J. EILEEN BIRD, EDDIE C. K. LIU, PATRICIA M. ROSE, RANDY SERAFINO, PHILIP D. STEIN and SUZANNE MORELAND. BMS-182874 is a selective, nonpeptide endothelin ETA receptor antagonist. JPET 272:1124-1134, 1995.