The potential role for lixivaptan in heart failure and in hyponatremia

Abstract

The available experience of lixivaptan in heart failure, although limited, is encouraging. Its aquaretic effect provides the basis for its use to correct hypervolemia and hyponatremia in patients with heart failure, and the absence of neurhormonal stimulation provides positive signal for the exploration of its potential in improving outcomes.

An Improved, Scalable and Impurity-Free Process for Lixivaptan

“…The intermediate 8 was afforded by filtration as yellow powder (470 g, yield 84%), mp 135-138°C. 1 (4-Amino-2-chlorophenyl)-5H-pyrrolo[2,1-c] [1,4]benzodiazepin-10(11H)-yl-methanone (9). The mixture of 8 (450 g, 1.2 mol) and 5% Pd/C (23 g) in N,N-dimethylformamide (1400 mL) was stirred at 35~40°C for 6 h under hydrogen atmosphere.…”

“…Lixivaptan is an oral, nonpeptide vasopressin V2 receptor antagonist applied in the treatment of hyponatremia [1][2][3][4][5][6]. Recent reports demonstrated that it might have benefits to patients with congestive heart failure [7][8][9][10], cirrhosis [11], and syndrome of inappropriate antidiuretic hormone secretion [12,13]. It is chemically known as N-[3-chloro-4-(5H-pyrrolo [2,1-c] [1,4]benzodiazepine-10(11H)-ylcarbonyl)phenyl]-5-fluoro-2-methylbenzamide, which is represented by chemical formula in Figure 1.…”

Hyponatremia in chronic heart failure

“…Rezultati utjecaja na patofizioloπke osnove SZ kao kompleksnog poremeÊaja, sposobnost djelovanja na remodeling miokarda te dugoroËni utjecaj na kliniËki tijek i ishod za sada se mogu promatrati kroz niz manjih kliniËkih studija. Potrebna su dodatna istraaeivanja za konaËno definiranje navedenih pitanja i formulaciju stava o poziciji ove skupine lijekova u ukupnom lijeËenju SZ [14][15][16] . dium levels, primarily by thiazide diuretics that exert effect on the distal tubules.…”

“…the clinical course and outcome can now be observed in series of small clinical studies. Additional trials are required to finally define these issues and to take an attitude towards the position of this group of drugs in the overall treatment of HF [14][15][16] . Particular attention is to be paid to the patients with hypovolemic hyponatremia in the correction of hyponatremia as a part of the HF syndrome 4,17 .…”

Assessment of Exposure of Metabolites in Preclinical Species and Humans at Steady State from the Single-Dose Radiolabeled Absorption, Distribution, Metabolism, and Excretion Studies: A Case Study

“…Lixivaptan [1,4]-benzodiazopin-10(11H)-ylcarbonyl)-3-chlorophenyl]-benzamide) is a potent, selective, orally active, nonpeptide competitive vasopressin V2 receptor antagonist Chan et al,1998;Ashwell et al, 2000;Zmily et al, 2011). It is currently being developed for the treatment of hyponatremia associated with syndrome of inappropriate antidiuretic hormone secretion and heart failure.…”