Tolvaptan

Substances which promote the elimination of water by the kidney without major losses of salts (e.g. con-ivaptan, tolvaptan, SR121463A/B). They are particularly useful in situations where excess water needs to be eliminated without affecting the salt metabolism, like eu- or hypervolemic hyponatraemia, congestive heart failure, some stages of hypertension and some metabolic states. 

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). 

Several selective V2R antagonists have also been developed (tolvaptan, lixivaptan, OPC-31260, Satavaptan, RWJ-351647). These substances, together with conivaptan, are also known as aquaretic agents . 

Catalytic reduction of the nitro group proceeds to the aniline (4-9). The chain is next extended by acylation of the newly formed amine with ortho-toluyl chloride (4-10) to give (4-11). Reduction of the azepinone carbonyl group with borohydride affords the vasopressin antagonist tolvaptan (4-12) [5]. 

Antidiuretic hormone antagonists are used to manage SIADH when water restriction has failed to correct the abnormality. This generally occurs in the outpatient setting, where water restriction cannot be enforced, or in the hospital when large quantities of intravenous fluid are needed for other purposes. Lithium carbonate has been used to treat this syndrome, but the response is unpredictable. Demeclocycline, in dosages of 600-1200 mg/d, yields a more predictable result and is less toxic. Appropriate plasma levels (2 mcg/mL) should be maintained by monitoring. Unlike demeclocycline, conivaptan is administered by IV injection, so it is not suitable for chronic use in outpatients. Lixivaptan and tolvaptan should soon be available for oral use. 

A group of nonpeptide antagonists of vasopressin receptors is being investigated for use in patients with hyponatremia or acute heart failure, which is often associated with elevated concentrations of vasopressin. Conivaptan has high affinity for both Vla and V2 receptors. Tolvaptan has a 30-fold higher affinity for V2 than for Vi receptors. In several clinical trials,... 

Tolvaptan Similar but more selective for vasopressin V2 receptors... 

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). 

In a double-blind placebo-controlled study of the effects of three doses of tolvaptan (30, 45, or 60 mg/day) in 254 patients with chronic heart failure taking stable doses of furosemide there were significant reductions in body weight and increased urine volumes edema improved and serum sodium normalized in those with hyponatremia (5). There were no significant changes in heart rate, blood pressure, serum potassium, or renal function. 

In two multicenter, randomized, double-blind, placebo-controlled studies of tolvaptan in 448 patients with euvolemic or hypervolemic hyponatremia, tolvaptan 15-60 mg/day increased serum sodium concentrations significantly compared with placebo (6). The main adverse effects associated with tolvaptan included increased thirst, dry mouth, and increased urination. 

In a multicenter randomized, double-blind, placebo-controlled study in 4133 patients with heart failure, tolvaptan 30 mg/day for a minimum of 60 days in addition to standard therapy significantly improved dyspnea, body weight, and edema in patients with hyponatremia, serum sodium concentrations increased significantly (7). The main adverse effects were increased thirst and a dry mouth. 

In two double-blind, randomized, placebo-controlled studies in 17 subjects in all, the main adverse effects of tolvaptan 60-240-mg/day were excess thirst, frequent urination, and a dry mouth (8). 

Gheorghiade M, Niazi I, Ouyang J, Czerwiec F, Kambayashi J, Zampino M, Orlandi C Tolvaptan Investigators. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure results from a double-blind, randomized trial. Circulation 2003 107(21) 2690-6. 

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. 

Shoaf SE, Wang Z, Bricmont P, Mallikaarjun S. Pharmacokinetics, pharmacodynamics, and safety of tolvaptan, a nonpeptide AVP antagonist, during ascending singledose studies in healthy subjects. J Clin Pharmacol 2007 47(12) 1498-507. 

Shoaf SE, Bramer SL, Bricmont P, Zimmer CA. Pharmacokinetic and pharmacodynamic interaction between tolvaptan, a non-peptide AVP antagonist, and fur-osemide or hydrochlorothiazide. J Cardiovasc Pharmacol 2007 50(2) 213-22. 

As Of 2009, conivaptan HCl (1) is one of three vasopressin receptor antagonists approved for use in the treatment of hyponatremia worldwide. The U.S. approval of 1 was preceded by the 2006 approval of mozavaptan hydrochloride (2) in Japan. In 2009, tolvaptan (3) joined 1 as an FDA-approved agent for the treatment of hyponatremia. In this chapter, the pharmacological profile and synthesis of conivaptan hydrochloride (1) is examined in detail. 

USAN Tolvaptan Trade name Samsca Otsuka Pharmaceutical Co. Launched 2009... 

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. 

Taltobulin, 11 Tamibarotene, 76 Tandutinib, 183 Tanomastat, 47 Tezacitabine, 131 Tipifamib, 172 Topixantrone, 227 Troxacitabine, 131 Vandetanib, 181 Antipsoriatic Ecalcidine, 38 Antiviral Amdoxovir, 199 Amprenavir, 4 Aplaviroc, 134 Atazanavir, 7 Capravirine, 95 Clevudine, 130 Daninavir, 5 Efavirenz, 177 Emivirine, 123 Emtricitabine, 132 Etravirine, 123 Fosamprenavir, 6 Lopinavir, 7 Maraviroc, 107 Maribavir, 158 Omaciclovir, 199 Oseltamivir, 25 Peramavir, 53 Rupinavir, 9 Tenofovir, 197 Tiprinavir, 120 Anxiolytic Sunepitron, 209 Apetite Supressant Rimonabant, 99 Cardiotonic Naxifylline, 203 Torborinone, 172 Collagenase Inhibitor Cipemastat, 99 Diuretic Lixivaptan, 222 Tolvaptan, 186 Elastase Inhibitor Sivelstat, 54... 

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