Vasopressin V2 antagonist

Logically, ADH receptor antagonists, and ADH synthesis and release inhibitors can be effective aquaretics. ADH, 8-arginine vasopressin [113-79-17, is synthesized in the hypothalamus of the brain, and is transported through the supraopticohypophyseal tract to the posterior pituitary where it is stored. Upon sensing an increase of plasma osmolaUty by brain osmoreceptors or a decrease of blood volume or blood pressure detected by the baroreceptors and volume receptors, ADH is released into the blood circulation it activates vasopressin receptors in blood vessels to raise blood pressure, and vasopressin V2 receptors of the nephrons of the kidney to retain water and electrolytes to expand the blood volume. 

Inhibition of V2 vasopressin receptors causes an increase in urine volume primarily by reducing the re-absoiption of water along the collecting duct, an aquaretic effect that is fundamentally different from the natriuretic actions discussed so far. Nevertheless, some of the conditions calling for the use of natriuretic intervention are identical to those in which the administration of a new class of orally active nonpeptide V2 antagonists may be useful (tolvaptan, lixivaptan, and others). 

A vasopressin V2 receptor antagonist, lixivaptan, is currently being developed (Phase 11) for the treatment of hyponatremia. This agent blocks the effect of the antidiuretic hormone arginine-vasopressin. 

Vasopressin receptor antagonists, such as relcovaptan (an antagonist at Vla receptors), lixivaptan and tolvaptan (V2), and conivaptan (mixed V a/V2), are also under development (1). 

Serradeil-Le Gal C, Wagnon J, Valette G, Garcia G, Pascal M, Maffrand JP, Le Fur G. Nonpeptide vasopressin receptor antagonists development of selective and orally active Via, V2 and Vlb receptor ligands. Prog Brain Res 2002 139 197-210. 

Ghali JK, Koren MJ, Taylor JR, Brooks-Asplund E, Fan K, Long WA, Smith N. Efficacy and safety of oral conivaptan a V1A/v2 vasopressin receptor antagonist, assessed in a... 

Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006 355(20) 2099-112. 

Enzymatic reactions now have a sound place in contemporary synthetic methodology. Illustrative of this, lipase-catalyzed transesterification of the racemic alcohol 65 has been used effectively to produce (6)-(+)-66 (LipaseQL, 0-5 °C, 4 h 47% yield >99% ee), plus the (R)-(—)-acetoxy derivative 67 (Equation 8). The 1-benzazepine derivative 66 was then converted to a chiral precursor required for the synthesis of the nonpeptide vasopressin V2 receptor agonist, OPC-51803 <2002H(58)635>. The synthesis of a 1-benzazepine-based antagonist (OPC-41061) at this receptor has also been reported <2002H(56)123>. 

Due to the dual renal and vascular action of AVP, scientists at Yamanouchi Pharmaceuticals became interested in the identification of dual Vla/V2 vasopressin receptor antagonists, particularly because such agents were anticipated to be of unique utility in the treatment of congestive heart failure (CHF), where aberrant AVP secretion appeared responsible for both the onset of hypervolemic hyponatremia and deleterious increases in vascular resistance.14 The resulting drug discovery program ultimately lead to the identification of conivaptan HCl (1). 

In CHO cells transfected with human V], and V2 vasopressin receptors, 1 inhibits [3H]-AVP binding with K/s of 4.3 and 1.9 nM, respectively.15 Compound 1 demonstrates similar activity on rat Vla and V2 receptors, with Kj s of 0.48 nM and 3.0 nM (Table 1). As a result of significant structural homology between the vasopressin and the oxytocin receptors, 1 and AVP also demonstrate significant oxytocin receptor affinities (rat receptor Kt s of 44.4 nM and 3.4 nM, respectively).16 As seen in Table 1, the balanced binding affinities of 1 toward rat Via and V2 receptors closely parallel those of AVP in contrast, vasopressin receptor antagonists mozavaptan hydrochloride (2) and tolvaptan (3) demonstrate moderate to significant V2 receptor selectivity. 

Conivaptan HCl (1) is a potent dual Vla and V2 vasopressin receptor antagonist that increases water excretion without significant electrolyte depletion. 

Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progres- 399. sion by a vasopressin V2 receptor antagonist. Nature Med 2003 9 1323-6. 

Satavaptan [36], a vasopressin V2 receptor antagonist was developed as a potential treatment for hyponatremia in syndrome of inappropriate secretion of antidiuretic hormone (SIADH, Schwartz-Bartter syndrome) and cirrhotic ascites. However, by Febmary 2009, development was terminated for both indications. 

Gines P, Wong F, Watson H, Terg R, Bruha R, Zarski JP, Dudley F Normo-CAT Study Investigators. Clinical trial short-term effects of combination of sata-vaptan, a selective vasopressin V2 receptor antagonist, and diuretics on ascites in... 

Wong F, Gines P, Watson H, Horsmans Y, Angeli P, Gow P, Minini P, Bernardi M. Effects of a selective vasopressin V2 receptor antagonist, satavaptan, on ascites recurrence after paracentesis in patients with cirrhosis. J Hepatol 2010 53(2) 283-90. 

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