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

  • Peter S. Chan
  • Joseph Coupet
  • Hyung C. Park
  • Fong Lai
  • Dale Hartupee
  • Peter Cervoni
  • John P. Dusza
  • Jay D. Albright
  • Xun Ru
  • Hossein Mazandarani
  • Tarak Tanikella
  • Cherrie Shepherd
  • Laura Ochalski
  • Trina Bailey
  • Tim Yeung Wai Lock
  • Xiaoping Ning
  • Joseph R. Taylor
  • Walter Spinelli
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 449)

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 Vz 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 V1a/V2 receptor antagonist.

Keywords

Oxytocin Receptor Vasopressin Antagonist Conventional Diuretic Plasma Vasopressin Concentration Manning Compound 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Peter S. Chan
    • 1
  • Joseph Coupet
    • 1
  • Hyung C. Park
    • 1
  • Fong Lai
    • 1
  • Dale Hartupee
    • 1
  • Peter Cervoni
    • 1
  • John P. Dusza
    • 1
  • Jay D. Albright
    • 1
  • Xun Ru
    • 1
  • Hossein Mazandarani
    • 1
  • Tarak Tanikella
    • 1
  • Cherrie Shepherd
    • 1
  • Laura Ochalski
    • 1
  • Trina Bailey
    • 1
  • Tim Yeung Wai Lock
    • 1
  • Xiaoping Ning
    • 1
  • Joseph R. Taylor
    • 1
  • Walter Spinelli
    • 1
  1. 1.Wyeth-Ayerst ResearchPrincetonUSA

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