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CHARACTERIZATION OF RWJ‐351647, A NOVEL NONPEPTIDE VASOPRESSIN V 2 RECEPTOR ANTAGONIST
Author(s) -
Gunnet Joseph W,
Matthews Jay M,
Maryanoff Bruce E,
De Garavilla Lawrence,
AndradeGordon Patricia,
Damiano Bruce,
Hageman William,
Look Richard,
Stahle Paul,
Streeter Anthony J,
Wines Pamela G,
Demarest Keith T
Publication year - 2006
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2006.04369.x
Subject(s) - receptor , agonist , antagonist , vasopressin , endocrinology , receptor antagonist , pharmacology , medicine , chemistry , in vivo , vasopressin receptor , biology , microbiology and biotechnology
SUMMARY1 Antagonists of the V 2 vasopressin (AVP) receptor are aquaretic agents, inhibiting water resorption without stimulating electrolyte excretion. In this set of experiments, a novel V 2 receptor antagonist, RWJ‐351647, was characterized in vitro and in vivo . 2 RWJ‐351647 displaced 3 H‐AVP binding from cloned human V 2 and V 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 2 receptors, RWJ‐351647 inhibited AVP‐induced cAMP accumulation with Ki values of 3 nmol/L and 6 nmol/L, respectively. 3 RWJ‐351647 was very selective in binding assays and showed only weak functional antagonist activity at either the cloned human V 1B and oxytocin receptors or the human platelet V 1A receptor. No agonist activity was seen with the compound at any receptor. 4 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. 5 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. 6 In summary, RWJ‐351647 was shown to be a selective and potent V 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.