Patent Evaluation: Novel Endothelin Receptor Antagonists Isolated from Microbispora

Summary

Novelty: Three novel cyclic depsipeptides derived from a culture of Microbispora sp. MA6857 are claimed as endothelin receptor antagonists. They are claimed for the treatment of cardiovascular disorders, including hypertension, cerebral and cardiac ischaemia and postischaemic venal failure, and for the treatment of asthma and of cyclosporin nephrotoxicity.

Biology: The binding of the cyclopeptides was determined in a method similar to the assay described by Ambar et al. (Biochem. Biophys. Res. Comm. (1989) 158:195-201) and by Khoog et al. (FEBS Letters (1989) 253:199-202); the method is fully described. Results for rat aorta and rat hippocampus binding are presented. The specified compound had K_is against ¹²⁵I-endothelin I binding of 100 nM (aorta) and 200 nM (hippocampus).

Chemistry: Three cyclic depsipeptides are specifically claimed. Detailed ¹H and ¹³C nmr data are given. Experimental details for the isolation of the claimed compounds from cultures of Microbispora are presented.

Structure: