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A novel class of endothelin-A receptor ligands was discovered by high-throughput screening. Lead structure optimization led to highly potent antagonists which can be synthesized in a short sequence. The compounds are endothelin-A-selective, are orally available, and show a long duration of action.
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… (More)
Structural variation of the endothelin A-selective antagonist (S)-3-methoxy-2-(4,6-dimethoxypyrimidin-2-yloxy)-3, 3-diphenylpropionic acid (LU 135252) led to analogues which retain ET(A) affinity but exhibit substantial ET(B) affinity as well. The most active derivative obtained is (S)-3-[2-(3, 4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)- 3,… (More)
In a clinical controlled study involving more than 100 patients with nonarticular rheumatism, the nonsteroidal anti-inflammatory agent Ibuprofen Klinge 600 proved clinically effective. The test parameters were subjective pain considered separately as pain at rest, pain on movement, and tenderness, and the time to appearance of fatigue. All three categories… (More)