NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONISTS .6. PHARMACOLOGICAL CHARACTERIZATION OF SE-217242, A POTENT AND HIGHLY BIOAVAILABLE ENDOTHELIN RECEPTOR ANTAGONIST

This study describes the pharmacological characterization of SE 217242 , a highly potent orally bioavailable nonpeptide antagonist of both en dothelin type A (ET(A)) and endothelin type B (ET(B)) receptors. In hu man cloned ET(A) and ET(B) receptors, SE 217242 produced concentration -dependent displacement of [(125)]I-endothelin-1 (ET-1) in both recept or subtypes with K-i values of 1.1 and 111 nM, respectively. SE 217242 produced concentration-dependent, parallel rightward shifts in the ET -1 concentration-response curves in rat isolated aorta and human isola ted pulmonary artery (ET(A) receptor-mediated vascular contraction) wi th K-b values of 4.4 and 5.0 nM, respectively. SB 217242 was 4-, 62- a nd 125-fold more potent as an ET(A) receptor antagonist than the previ ously reported compounds BQ-123, PD 142893 and Ro 46-2005, respectivel y. SB 217242 (10 mu M) did not produce significant effects against con traction produced by other vasoactive agents. SE 217242 produced conce ntration-dependent antagonism of responses produced by ET(B) receptor activation as demonstrated by antagonism of sarafotoxin S6c-mediated c ontraction in the rabbit isolated pulmonary artery with a K-b value of 352 nM. In vitro cell monolayers of Caco-2 cells had high permeabilit y to SE 217242. In vivo pharmacokinetics in the rat confirmed that SE 217242 was rapidly absorbed from the gastrointestinal tract with a bio availability of 66%. The SE 217242 plasma half-life in rats after intr aduodenal administration was 3.3 hr, with a systemic clearance of 27.3 ml/min/kg. Orally administered SE 217242 (0.3-30 mg/kg) produced dose -dependent inhibition of the presser response to exogenous ET-1 in con scious rats; with a dose of 30 mg/kg p.o., inhibition was observed for at least 5.5 hr. The present study demonstrates that SE 217242 is a h ighly potent antagonist of both ET(A) and ET(B) receptors. In addition , SB 217242 has high in vitro permeability and high oral bioavailabili ty. SE 217242 represents a new orally active pharmacological tool that should assist in the elucidation of the chronic role of endothelin in pathophysiology.