Vasopressins antagonists

Lemmens-Gruber R, Kamyar M (2006) Vasopressin antagonists. Cell Mol Life Sci 63 1766-1779... 

The search for an effective non-peptide oxytocin antagonist has become a major goal of a number of pharmaceutical companies because of the poor pharmacokinetic properties and especially the lack of oral bioavailability associated with peptidic antagonists. Early research in this field was dominated by Merck, but in recent years significant research efforts at GlaxoSmithKline and Serono have been published. A number of other companies, notably Sanofi-Aventis, Yamanouchi and Wyeth, have had a major presence in vasopressin receptor research and oxytocin is frequently included in patent claims for the molecules. Occasionally, oxytocin-selective compounds have been reported, usually derived by adaptation of the vasopressin antagonist template. 

Ovarian hormones influence fluid intake by interaction with the brain renin-angiotensin system and it has been shown that gonadal steroids affect brain fluid-electrolyte balance by interactions with vasopressin. Both hyperos-molarity and increased intracranial pressure stimulate vasopressin release and intraperitoneal administration of vasopressin antagonists decrease brain volume. 

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]. 

Medullary collecting duct Water reabsorption under vasopressin control Variable2 Aquaporins Vasopressin antagonist... 

Hays RM Vasopressin antagonists Progress and promise. N Engl 3 Med 2006 355 146. 

Thibonnier, M. (199CQ Vasopressin agonists and antagonists. Harm. J2es..34.124-128. Laszto, F.A. etal. (1991) Pharmacolocy and clinical perspectives of vasopressin antagonists. Pharmacol. Rev.. 43.7J -108. 

Matsuhisa, A., Taniguchi, N., Koshio, H., Yatsu, T., Tanaka, A. Nonpeptide arginine vasopressin antagonists for both VIA and V2 receptors synthesis and pharmacological properties of 4 -(l,4,5, 6-tetrahydroimidazo[4,5-d][l]benzazepine-6-carbonyl)benzanilide derivatives and 4 -(5,6-dihydro-4H-thiazolo[5,4-d][l]benzazepine-6-carbonyl)benzanilide derivative. Chem. Pharmaceut. Bull. 2000, 4S, 21-31. 

A new route for the synthesis of 50 (YM087), an arginine vasopressin antagonist, has been reported by Tsunoda et al. <04H(63)1113>. The imidazolobenzazepine 49 was a key intermediate in this new route which involved benzazepinone formation from the amino ester 48 (obtained in turn in two steps from 47) followed by elaboration of the imidazole ring fusion. 

Arg ]-vasopressin stimulated surfactant secretion in primary cultures of rat type 2 pneumocytes independently of adenosine 3 ,5 -cyclic monophosphate (Brown and Wood 1989). A 50% loss of tritiated phosphatidyhnsositol 4,5-biphosphate (PIP2) occurred from cells prelabeled with myo[ H]inositol within 15 s (Brown and Chen 1990). Consistent with vasopressin-induced PIP2 hydrolysis the two breakdown products, 1,2-diacylglycerol and inositol 1,4,5-triphosphate, was observed. Vasopressin stimulated protein kinase C activity twofold over the basal activity of 0.7410.07 nM/min x mg protein. The [Arg ]-vasopressin antagonist, 1-deamino-8-D-arginine vasopressin, inhibited [Arg ]-vasopressin activation of protein kinase C. 

The mammalian suprachiasmatic nuclei contain an endogenous pacemaker that generates daily rhythms in behaviour and secretion of hormones. They stimulate evening ACTH secretion in the rat (Cascio etal. 1987). Kalsbeek etal. (1996) used microdialysis-mediated intracerebral administration of the vasopressin V,-receptor antagonist to study the mechanisms underlying the circadian control of basic corticosterone release in the rat. By timed administration of the vasopressin antagonist divided equally over the day/night cycle, they were able to uncover the existence of an additional stimulatory input from the suprachiasmatic nucleus to the hypothalamo-pituitary-adrenal axis. 

Cardenas A, Gines P, Marotta P, Czerwiec F, Oyuang J, Guevara M, et al. Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis. J Hepatol 2012 56(3) 571-8. 

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