RELCOVAPTAN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C28H27Cl2N3O7S
Molecular Weight	620.501
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=C(OC)C=C(C=C1)S(=O)(=O)N2[C@@H](C(=O)N3CCC[C@H]3C(N)=O)[C@](O)(C4=CC(Cl)=CC=C24)C5=C(Cl)C=CC=C5

InChI

InChIKey=CEBYCSRFKCEUSW-NAYZPBBASA-N

InChI=1S/C28H27Cl2N3O7S/c1-39-23-12-10-17(15-24(23)40-2)41(37,38)33-21-11-9-16(29)14-19(21)28(36,18-6-3-4-7-20(18)30)25(33)27(35)32-13-5-8-22(32)26(31)34/h3-4,6-7,9-12,14-15,22,25,36H,5,8,13H2,1-2H3,(H2,31,34)/t22-,25-,28+/m0/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/12436936
Curator's Comment: The description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/15823830 | https://www.ncbi.nlm.nih.gov/pubmed/14678081 | https://www.ncbi.nlm.nih.gov/pubmed/11035135

Relcovaptan is a potent, orally active nonpeptide vasopressin V1a antagonist that was undergoing clinical development with Sanofi-Synthélabo (formerly Sanofi) in France. SR49059 is specifically and selectively antagonizes the effect of vasopressin on the V1a receptor in animals’ and in humans. The drug has been shown to have an excellent safety profile in single and repeated dose toxicological studies in animals. In the human uterus in vitro, SR49059 caused a dose-dependent inhibition of vasopressin V1a receptor-mediated activity of myometrial strips and isolated uterine arteries. In vivo in nonpregnant women, an inhibition of vasopressin-induced uterine activity has been observed.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Vasopressin V1a receptor 17 Target ID: CHEMBL1889 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21885275	Antagonist 2778		13.0 nM [IC50]
Vasopressin V2 receptor 15 Target ID: CHEMBL1790 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12036368	Antagonist 2778		178.0 nM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
Preterm labor 3 Sources: https://www.ncbi.nlm.nih.gov/pubmed/14678081	Primary	Not Provided 504	Unknown Approved Use Unknown
Raynaud's disease 5 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11035135	Primary	Not Provided 504	Unknown Approved Use Unknown
Dysmenorrhea 9 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10826575	Primary	Not Provided 504	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
		252159999
Binding of [3H] SR 49059, a potent nonpeptide vasopressin V1a antagonist, to rat and human liver membranes.	1994 Feb 28	8123034
Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor.	1994 Feb 4	8106369
The human V3 pituitary vasopressin receptor: ligand binding profile and density-dependent signaling pathways.	1997 Oct	9322919
Mapping peptide-binding domains of the human V1a vasopressin receptor with a photoactivatable linear peptide antagonist.	1997 Oct 17	9334232
Pharmacological characterization of the human vasopressin receptor subtypes stably expressed in Chinese hamster ovary cells.	1998 Dec	9884074
Oxytocin and vasopressin constrict rat isolated uterine resistance arteries by activating vasopressin V1A receptors.	1999 Jul 2	10440088
Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women.	1999 Oct	10519430
Vasopressin does not effect hypertension caused by long-term nitric oxide inhibition.	2000 Feb	10679504
Conserved aromatic residues in the transmembrane region VI of the V1a vasopressin receptor differentiate agonist vs. antagonist ligand binding.	2000 Jul	10866830
Nitric oxide, but not vasopressin V2 receptor-mediated vasodilation, modulates vasopressin-induced renal vasoconstriction in rats.	2000 Mar	10731046
Binding properties of a selective tritiated vasopressin V2 receptor antagonist, [H]-SR 121463.	2000 Oct	11012895
High concentrations of oxytocin cause vasoconstriction by activating vasopressin V1A receptors in the isolated perfused rat kidney.	2001 Apr	11330329
Effects of YM471, a nonpeptide AVP V(1A) and V(2) receptor antagonist, on human AVP receptor subtypes expressed in CHO cells and oxytocin receptors in human uterine smooth muscle cells.	2001 Jul	11429400
Vascular and renal effects of vasopressin and its antagonists in conscious rats with chronic myocardial infarction; evidence for receptor shift.	2001 Jul 6	11448485
A nonpeptide vasopressin V(1a) receptor antagonist, SR 49059, does not prevent cisplatin-induced emesis in piglets.	2001 Jun	11468030
Placental transfer of SR49059 in the human dually perfused cotyledon in vitro.	2001 Nov	11718575
Effects of nonpeptide V(1) vasopressin receptor antagonist SR-49059 on infarction volume and recovery of function in a focal embolic stroke model.	2002 Dec	12468809
Interplay between presynaptic and postsynaptic activities is required for dendritic plasticity and synaptogenesis in the supraoptic nucleus.	2002 Jan 1	11756510
Vasopressin-induced facilitation of adrenergic responses in the rat mesenteric artery is V1-receptor dependent.	2003 Feb	14565536
Oxytocin and fetal membranes in preterm labor: current concepts and clinical implication.	2003 Jun	12857435
Identification of the binding sites of the SR49059 nonpeptide antagonist into the V1a vasopressin receptor using sulfydryl-reactive ligands and cysteine mutants as chemical sensors.	2003 Oct 10	12869559
Pancreatic vasopressin V1b receptors: characterization in In-R1-G9 cells and localization in human pancreas.	2003 Sep	12736162
Participation of vasopressin in the development of cerebral vasospasm in a rat model of subarachnoid haemorrhage.	2004 Apr	15053824
Functional rescue of the constitutively internalized V2 vasopressin receptor mutant R137H by the pharmacological chaperone action of SR49059.	2004 Aug	15166253
Inhibitory effects of SR 49059 on oxytocin-and vasopressin-induced uterine contractions in non-pregnant women.	2004 Jan	14678081
Vasotocin and vasopressin stimulation of the chloride secretion in the human bronchial epithelial cell line, 16HBE14o-.	2005 Apr	15685210
The effect of relcovaptan (SR 49059), an orally active vasopressin V1a receptor antagonist, on uterine contractions in preterm labor.	2005 Feb	15823830
Pharmacologic properties of YM218, a novel, potent, nonpeptide vasopressin V1A receptor-selective antagonist.	2005 Jan	15722249
Selectivity of d[Cha4]AVP and SSR149415 at human vasopressin and oxytocin receptors: evidence that SSR149415 is a mixed vasopressin V1b/oxytocin receptor antagonist.	2005 Nov	16158071
Protective effect of the V1a receptor antagonist SR49059 on brain edema formation following middle cerebral artery occlusion in the rat.	2006	16671476
Vasopressin receptor antagonists: pharmacological tools and potential therapeutic agents.	2006 Apr	16553642
Evidence for a role of vasopressin in the control of aldosterone secretion in primary aldosteronism: in vitro and in vivo studies.	2006 Apr	16449345
Vasopressin antagonists.	2006 Aug	16794787
Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus.	2006 Jan	16319185
Effects of YM218, a nonpeptide vasopressin V(1A) receptor-selective antagonist, on vasopressin-induced growth responses in human mesangial cells.	2006 May 24	16678155
Pharmacological chaperone activity of SR49059 to functionally recover misfolded mutations of the vasopressin V1a receptor.	2006 May 26	16565083
Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus.	2007 Jan	16926443
The modulation of aquaporin-4 by using PKC-activator (phorbol myristate acetate) and V1a receptor antagonist (SR49059) following middle cerebral artery occlusion/reperfusion in the rat.	2008	19388361
Modulation of AQP4 expression by the selective V1a receptor antagonist, SR49059, decreases trauma-induced brain edema.	2008	19388360
Effects of novel vasopressin receptor antagonists on renal function and cardiac hypertrophy in rats with experimental congestive heart failure.	2008 Aug	18467593
Non-peptide arginine-vasopressin antagonists: the vaptans.	2008 May 10	18468546
[Vasopressin receptor antagonists and heart failure].	2009 Nov	19885790
cAMP/PKA-dependent increases in Ca Sparks, oscillations and SR Ca stores in retinal arteriolar myocytes after exposure to vasopressin.	2010 Mar	19959643

Patents

Sample Use Guides

In Vivo Use Guide

25, 75 or 200 mg

Route of Administration: Oral

In Vitro Use Guide

MDCK II cells were seeded on 12 multiwell filters (Costar) at a density of 150,000 cells/cm2 and grown for 3 days. Cells were subsequently treated with the antagonists for 16 h, followed by three washes with ice-cold phosphate-buffered saline containing 1 mM MgCl2 and 0.1 mM CaCl2 (PBS-CM). The cells were then incubated for 1 h on ice with [3H]AVP (PerkinElmer Life Sciences, Boston, MA) and the antagonist (Relcovaptan) diluted in PBS-CM. Cells were washed three times with ice-cold PBS-CM, followed by excision of the filters and counting of the radioactivity

Name

Type

Language

RELCOVAPTAN

Official Name

English

relcovaptan [INN]

Common Name

English

2-PYRROLIDINECARBOXAMIDE, 1-(((2R,3S)-5-CHLORO-3-(2-CHLOROPHENYL)-1-((3,4-DIMETHOXYPHENYL)SULFONYL)-2,3-DIHYDRO-3-HYDROXY-1H-INDOL-2-YL)CARBONYL)-, (2S)-

Common Name

English

(2S)-1-(((2R,3S)-5-CHLORO-3-(O-CHLOROPHENYL)-1-((3,4-DIMETHOXYPHENYL)SULFONYL)-3-HYDROXY-2-INDOLINYL)CARBONYL)-2-PYRROLIDINECARBOXAMIDE

Common Name

English

SR-49059

Code

English

SR49059

Code

English

TDI-0134

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C2180