Recent developments of small molecule endothelin modulators

Endothelin (ET) receptor antagonists, in particular endothelin ETA-selective or ETA/ETB balanced antagonists, represent a novel new class of therapeutic agents. They have demonstrated utility or promise for unmet medical needs such as pulmonary hypertension, resistant hypertension, heart failure, diabetic nephropathy and subarachnoid haemorrhage. Oral endothelin antagonist-based treatments, either as monotherapy or in combination with agents of other mechanisms of action, should afford benefits to those patients. The importance of this field is evidenced by the number of compounds in clinical trials (i.e., 8) and by the number of patents filed in recent years. Between January 2002 and September 2005, there were 46 endothelin patents, of which 38 are concerned with endothelin receptor antagonists (ETRAs) and 8 with endothelin-converting enzyme (ECE) inhibitors/ET secretion inhibitors. Of the 38 ETRA patents, 12 disclose new chemical structures, 5 disclose processes, 11 disclose new uses and 10 disclose combination therapies. This article first discusses small-molecule endothelin antagonists presently in the clinic and then focuses on the 20 novel composition-of-matter patents in the area of ETRA, ECE inhibitors and ET secretion inhibitors.