Lixivaptan

Lixivaptan
Clinical data
ATC code	none;
Identifiers
	IUPAC name N-[3-chloro-4-(6,11-dihydropyrrolo[2,1-c][1,4]benzodiazepine-5-carbonyl)phenyl]-5-fluoro-2-methylbenzamide;
CAS Number	168079-32-1 ;
PubChem CID	172997;
IUPHAR/BPS	2238;
ChemSpider	151067 ;
UNII	8F5X4B082E;
ChEMBL	ChEMBL49429 ;
CompTox Dashboard (EPA)	DTXSID00168472 ;
ECHA InfoCard	100.126.016
Chemical and physical data
Formula	C27H21ClFN3O2
Molar mass	473.93 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1c2cccn2Cc3ccccc3N1C(=O)c4ccc(cc4Cl)NC(=O)c5cc(F)ccc5C;
	InChI InChI=1S/C27H21ClFN3O2/c1-17-8-9-19(29)13-23(17)26(33)30-20-10-11-22(24(28)14-20)27(34)32-16-21-6-4-12-31(21)15-18-5-2-3-7-25(18)32/h2-14H,15-16H2,1H3,(H,30,33) ; Key:PPHTXRNHTVLQED-UHFFFAOYSA-N ;
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Lixivaptan (VPA-985) is a phase III pharmaceutical being developed by Cardiokine, Inc., a specialty pharmaceutical company based in Philadelphia, PA, focused on the development of pharmaceuticals for the treatment and prevention of cardiovascular diseases. Lixivaptan is, as of May 2010, in Phase III clinical trials involving patients with hyponatremia, including those with concomitant heart failure.[1] Hyponatremia is an electrolyte disturbance in which the sodium concentration in the serum is lower than normal. Lixivaptan may help some patients eliminate excess fluids while retaining electrolytes.

Chemistry

Lixivaptan is synthesized as follows:[2]

Mechanism of action

Lixivaptan is a potent, non-peptide, selective vasopressin 2 receptor antagonist. The oral capsule works by reducing the action of the hormone vasopressin that blocks fluid excretion. Lixivaptan acts by blocking vasopressin, an anti-diuretic hormone that causes the kidneys to retain water. When the body needs to remain hydrated under certain conditions, vasopressin can have protective effects. But an excess of vasopressin is counterproductive in a body retaining too much fluid. The drug shows promise in treating heart failure in patients with hyponatremia.

THE BALANCE study

In February 2008, Cardiokine and its worldwide partner, Biogen Idec, initiated THE BALANCE (Treatment of HyponatrEmia BAsed on LixivAptan in N Yha class III/IV Cardiac patient Evaluation) study. THE BALANCE study is a 650-patient Phase III, global, multi-center, randomized, placebo-controlled, double-blind, study of lixivaptan for hyponatremia in patients with heart failure. The primary objective is to evaluate the safety and effectiveness of lixivaptan, when compared to the placebo, in increasing serum sodium from baseline in heart failure patients with hyponatremia.[3][4]

Previous studies

In previous studies, lixivaptan improved blood sodium levels, lowered body weight and increased urine volume. Those studies suggest that lixivaptan may play an important role in treating hyponatremia and the signs and symptoms of water retention associated with heart failure, Syndrome of Inappropriate Anti-Diuretic Hormone(SIADH), and Liver Cirrhosis with Ascites (LCWA). In clinical trials involving patients with water volume overload, lixivaptan resulted in correction of hyponatremia together with marked aquaresis.

Vaptans

The vasopressin receptor antagonists, dubbed vaptans, target the vasopressin hormonal feedback system. Vasopressin, also called the anti-diuretic hormone or ADH, is an important part of regulation in the circulatory system and is integral to the balance of water in the body. As a fundamental part of hormonal control in the body, it is implicated in many different conditions. Vaptans can be administered orally or intravenously. They work by competing for the active sites on cells meant for vasopressin binding—in this way, the vasopressin is blocked from acting, which earns the title of vasopressin antagonists.

References

Ku E, Nobakht N, Campese VM (May 2009). "Lixivaptan: a novel vasopressin receptor antagonist". Expert Opinion on Investigational Drugs. 18 (5): 657–62. doi:10.1517/13543780902889760. PMID 19379124.
Albright JD, Reich MF, Delos Santos EG, Dusza JP, Sum FW, Venkatesan AM, et al. (July 1998). "5-Fluoro-2-methyl-N-[4-(5H-pyrrolo[2,1-c]-[1, 4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]benzamide (VPA-985): an orally active arginine vasopressin antagonist with selectivity for V2 receptors". Journal of Medicinal Chemistry. 41 (14): 2442–4. doi:10.1021/jm980179c. PMID 9651149.
Clinical trial number NCT00578695 for "THE BALANCE Study: Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation" at ClinicalTrials.gov
Abraham WT, Aranda JM, Boehmer JP, Elkayam U, Gilbert EM, Gottlieb SS, et al. (October 2010). "Rationale and design of the treatment of hyponatremia based on lixivaptan in NYHA class III/IV cardiac patient evaluation (THE BALANCE) study". Clinical and Translational Science. 3 (5): 249–53. doi:10.1111/j.1752-8062.2010.00217.x. PMC 5439626. PMID 20973922.

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[pmid19379124-1] Ku E, Nobakht N, Campese VM (May 2009). "Lixivaptan: a novel vasopressin receptor antagonist". Expert Opinion on Investigational Drugs. 18 (5): 657–62. doi:10.1517/13543780902889760. PMID 19379124.

[2] Albright JD, Reich MF, Delos Santos EG, Dusza JP, Sum FW, Venkatesan AM, et al. (July 1998). "5-Fluoro-2-methyl-N-[4-(5H-pyrrolo[2,1-c]-[1, 4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]benzamide (VPA-985): an orally active arginine vasopressin antagonist with selectivity for V2 receptors". Journal of Medicinal Chemistry. 41 (14): 2442–4. doi:10.1021/jm980179c. PMID 9651149.

[3] Clinical trial number NCT00578695 for "THE BALANCE Study: Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation" at ClinicalTrials.gov

[4] Abraham WT, Aranda JM, Boehmer JP, Elkayam U, Gilbert EM, Gottlieb SS, et al. (October 2010). "Rationale and design of the treatment of hyponatremia based on lixivaptan in NYHA class III/IV cardiac patient evaluation (THE BALANCE) study". Clinical and Translational Science. 3 (5): 249–53. doi:10.1111/j.1752-8062.2010.00217.x. PMC 5439626. PMID 20973922.