CHARACTERIZATION OF RWJ-351647, A NOVEL NONPEPTIDE VASOPRESSIN V sub(2) RECEPTOR ANTAGONIST

Antagonists of the V sub(2) vasopressin (AVP) receptor are aquaretic agents, inhibiting water resorption without stimulating electrolyte excretion. In this set of experiments, a novel V sub(2) receptor antagonist, RWJ-351647, was characterized in vitro and in vivo. RWJ-351647 displaced super(3)H-AVP binding from cloned human V sub(2) and V sub(1A) receptors with Ki values of 1 nmol/L and 24 nmol/L. In assays using transfected HEK293 cells expressing either human or rat V sub(2) receptors, RWJ-351647 inhibited AVP-induced cAMP accumulation with Ki values of 3 nmol/L and 6 nmol/L, respectively. RWJ-351647 was very selective in binding assays and showed only weak functional antagonist activity at either the cloned human V sub(1B) and oxytocin receptors or the human platelet V sub(1A) receptor. No agonist activity was seen with the compound at any receptor. Pharmacokinetic studies in rats showed RWJ-351647 to be 41.9% bioavailable after a single oral administration. After repeated daily dosing over 5 days, the oral bioavailability remained at 43.9% with no change in the compound peak plasma levels or clearance rate. In efficacy studies, RWJ-351647 increased urine output and decreased urine osmolality with oral doses as low as 0.1 mg/kg and 1.0 mg/kg in rats and cynomolgus monkeys, respectively. In a multiple dose study in primates, RWJ-351647 maintained a consistent aquaretic effect over 10 days without increasing sodium or potassium excretion. In summary, RWJ-351647 was shown to be a selective and potent V sub(2) receptor antagonist with sustainable aquaretic activity in both rats and primates. The preclinical data suggest that RWJ-351647 is a potent and effective aquaretic agent with potential for use in diseases characterized by water retention.