PD-156707: A selective endothelin-A receptor antagonist

PD 156707 is a highly potent, specific antagonist of the ET, receptor discovered as the result of directed structure-activity studies and lead optimization of a chemical library screen hit. Initial characterization included a logical progression from receptor binding studies through functional assays in vitro and in vivo. Despite a short terminal elimination half-life, the drug has good oral bioavailability and is well suited to chronic oral dosing. Where difficulties have been observed with food admiring, efficacy studies have utilized subcutaneous pellet technology or involved a closely related butenolide ET, receptor antagonist (PD 155080). The drug has been tested in a number of whole-animal disease models with efficacy demonstrated in heart failure, stroke, and pulmonary hypertension. Blood pressure lowering was not observed in cardiovascular safety studies or in a model of hypertension, nor was there evidence of benefit in models of acute renal failure, chronic renal failure, atherosclerosis or myocardial ischemia/infarction. Further evaluations are indicated to determine the role of ET and its antagonism in restenosis. For those conditions where benefit was demonstrated, doses and plasma levels are summarized in Table 3. It can be seen that the single dose (2.7 mg/kg/h) that produced a significant reduction in cerebral infarction in the cat was associated with mean plasma level of 2.2 μg/ml. In heart failure, efficacy was seen in two models with levels as low as 41 and 50 ng/ml. It is in pulmonary hypertension that positive effects of the drug have been seen at the lowest plasma levels: 0.54 and 0.56 ng/ml in parenteral and oral studies, respectively. The importance of plasma @? levels becomes obvious in light of the findings from the toxicology studies in dogs where, although morbidity/mortality was not apparent until plasma concentrations exceeded 100 μg/ml, arterial pathology was seen with concentrations as low as 0.25 μg/ml. In beagle dogs, arterial lesions (principally in coronary vessels) were seen following administration of various xenobiotics, in particular, vasodilators (minoxidil, theobromine, hydralazine, adenosine agonists, and type III-phosphodiesterase inhibitors) and adrenergic amines (isoproterenol, norepinephrine, dopamine, and dobutamine) (9,10,22,27,34,35,50, 51,52). The picture is confounded by the observation that similar vascular lesions are reported to occur spontaneously in beagle dogs (9,20,47), although it is of note that the lesions occurring with PD 156707 were not seen in control animals. In all cases, such arterial lesions were characterized by medial hemorrhage and/or fibrinoid necrosis with associated medial/adventitial accumulation of inflammatory cells. Lesions were typically seen in small to medium-sized arteries and varied in severity from microscopic segmental lesions to locally extensive areas of circumferential necrosis with gross discoloration and/or hemorrhage. The development of these arterial lesions appears to be relatively species-specific, and the implications for cardiovascular risk in humans is unknown. It is also unknown whether canine coronary arteriopathy is a class effect of ET-receptor antagonists, a feature of selective antagonism of ET, receptors or a finding unique to PD 156707. Future development of PD 156707 will depend on full toxicologic and toxicokinetic characterization in a variety of species and demonstration of an adequate therapeutic margin for exposure in humans.