Receptor Selectivity of Endothelin Antagonists and Prevention of Vasoconstriction and Endothelin-Induced Sudden Death

The new endothelin (ET) receptor antagonist LU 127043 shows higher ETA affinity than BQ 123, Ro 46–2005, and BMS 182874, with a Ki of 6 nmol/L vs. 19, 28, and 57 nmol/L. ETA/ETB selectivity of LU 127043 of about 160 is comparable to that of BQ 123 (200) and is much greater than that of Ro 46–2005 (0.93) and SB 209670 (0.74). In rabbit aortic segments, LU 127043 shows ET antagonistic potency similar to that of BQ 123 and BMS 182874 (pA2 7.34 vs. 7.36 and 7.09), whereas SB 209670 is more potent (9.80). In rats, LU 127043 completely prevents the ET-1-induced sudden death due to coronary constriction, as indicated by a pronounced T-wave increase. With i.v. pretreatment, LU 127043 is as effective as SB 209670, whereas it is three times more active using 4 h oral pretreatment. Even 8 h after oral administration, LU 127043, in contrast to SB 209670, provides dose-dependent protection. Hence, LU 127043 is an example of a selective ETA antagonist with high oral availability and long duration of action. Because the in vivo efficacy of other high affinity ET antagonists is relatively low, further optimization for therapeutic use should concentrate on pharmacokinetic properties.