The therapeutic potential of PD156707 and related butenolide endothelin antagonists

Plasma concentrations of the peptide endothelin (ET) are elevated in several cardiovascular diseases. Animal studies suggest that activation of ET receptors may contribute to the increase in vascular resistance and remodelling of cardiovascular tissues that are characteristic of these pathologies. Antagonists of these receptors may therefore have important clinical potential. PD156707 (Parke-Davis) is one of a series of novel, orally-active butenolide endothelin antagonists and is highly selective for the ETA receptor. In man, this subtype mediates the profound vasoconstrictor effects of the ET peptides, and blockade of the ETA receptor may therefore produce beneficial vasodilatation. The advantage of selective ETA receptor antagonism is that it leaves unaffected vascular ETB receptors, which mediate vasorelaxation, and non-vascular ETB receptors, particularly in the lung and kidneys, which act to clear ET from the plasma. PD156707 exhibits subnanomolar affinity and greater than 1000-fold selectivity for human ETA receptors and potently inhibits ET-1-mediated vasoconstriction in human isolated blood vessels. In rats, PD156707 has good oral bioavailability (41%) and a relatively short terminal t1/2 of approximately 1 h. Structural analogues of PD156707 that have comparable selectivity and potency for the ETA receptor are reported to have even better oral bioavailability and longer plasma t1/2 values. Preclinical studies with PD156707 indicate efficacy in animal models of congestive heart failure (CHF), pulmonary hypertension (PH) and cerebral ischaemia. We await data from clinical trials to confirm the therapeutic potential of the ETA-selective butenolide antagonists in man.