Patent Evaluation: Novel endothelin antagonists as potential antihypertensives

Summary

Novelty: Novel peptides having endothelin antagonist activity are disclosed. The compounds are potentially useful for the prevention and treatment of endothelin mediated diseases such as hypertension, myocardial infarction, cerebral ischaemia and asthma.

Biology: An [¹²⁵I]-endothelin-1 binding assay, using a porcine aorta preparation, is described. The preferred compound has an IC₅₀ value of 2.3 nM. The same compound has an IC₅₀ for inhibitory response of 230 nM (rabbit aorta contractility preparation). An in vivo rodent endothelin-pressor response model is also described. The preferred compound shows a marked antagonistic response at 10mg/kg.

Chemistry: Four hundred and thirty-two peptide compounds are specifically exemplified. Preparative details using standard techniques are presented.