The therapeutic potential of PD156707 and related butenolide endothelin antagonists

Abstract

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 ET_A receptor. In man, this subtype mediates the profound vasoconstrictor effects of the ET peptides, and blockade of the ET_A receptor may therefore produce beneficial vasodilatation. The advantage of selective ET_A receptor antagonism is that it leaves unaffected vascular ET_B receptors, which mediate vasorelaxation, and non-vascular ET_B 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 ET_A 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 t_½ of approximately 1 h. Structural analogues of PD156707 that have comparable selectivity and potency for the ET_A receptor are reported to have even better oral bioavailability and longer plasma t_½ 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 ET_A-selective butenolide antagonists in man.

• butenolide
• cerebral ischaemia
• CI-1020
• congestive heart failure
• endothelin ETA receptor antagonist
• non-peptide
• PD156707
• pulmonary hypertension
• subarachnoid haemorrhage