VPA-985, a Nonpeptide Orally Active and Selective Vasopressin V₂ Receptor Antagonist

Abstract

The introduction of the thiazides as orally-active diuretics about forty years ago (1), and other more effective low-ceiling diuretics thereafter, revolutionized the treatment of edema, ascites, hypertension and related diseases. Later, the addition of potent high-ceiling (loop) and potassium-sparing diuretics provided clinicians with a wide choice of diuretics to eliminate retained sodium and water (2). However, it was soon evident that many patients became refractory to these saluretic agents and some developed hyponatremia (serum sodium < 130 mEq/L) (3, 4, 5). Hyponatremia also occurs in the syndrome of inappropriate antidiuretic hormone secretion (SIADH), in patients with congestive heart failure (CHF), liver cirrhosis with ascites, renal failure, and many other disorders where the plasma vasopressin concentrations are inappropriately high for any given plasma osmolality. Under these conditions, an aquaretic (water diuretic), not a conventional diuretic, would be the drug of choice to promote the excretion of the retained body water and to normalize plasma osmolality and sodium concentration (6, 7, 8). As vasopressin (AVP, antidiuretic hormone (ADH)) acting at V₂ receptors in the collecting ducts controls water re-absorption (7, 8), considerable effort has been spent over many years to develop vasopressin V_z receptor antagonists or agents that could inhibit the release of vasopressin from the posterior pituitary (8,9). Many peptide vasopressin analogs have been developed as vasopressin V₂ receptor antagonists, and two of them, SK&F 101926 and SK&F 105494, showed excellent V₂ antagonistic activity in many animal models, including nonhuman primates. Unfortunately, in humans, both compounds behaved as vasopressin V₂ agonists (9). Recently, three nonpeptidic and orally active vasopressin receptor antagonists have been described in the literature. The first two, OPC-31260 (10), and SR 121463A (11), are V₂ selective, while the third compound, YM087 (12), is a dual V_1a/V₂ receptor antagonist.