GAVESTINEL SODIUM

Details

Stereochemistry	ACHIRAL
Molecular Formula	C18H11Cl2N2O3.Na
Molecular Weight	397.187
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[Na+].[O-]C(=O)C1=C(\C=C\C(=O)NC2=CC=CC=C2)C3=C(N1)C=C(Cl)C=C3Cl

InChI

InChIKey=GRSDSTMFQHAESM-UHDJGPCESA-M

InChI=1S/C18H12Cl2N2O3.Na/c19-10-8-13(20)16-12(17(18(24)25)22-14(16)9-10)6-7-15(23)21-11-4-2-1-3-5-11;/h1-9,22H,(H,21,23)(H,24,25);/q;+1/p-1/b7-6+;

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/9083472
Curator's Comment: Description was created using several sources including: https://www.ncbi.nlm.nih.gov/pubmed/16340185; https://www.ncbi.nlm.nih.gov/pubmed/15831831

GV 150526A (gavestinel) is an investigational drug for a neuroprotective therapy of acute ischemic stroke within 6 hours of symptom onset. It is a potent and selective non-competitive antagonist at the glycine site of the N-methyl-D-aspartate receptor (NMDA) which reduces infarct volume in experimental stroke models. Gavestinel acts at the strychnine-insensitive glycine binding site of the NMDA receptor-channel complex with nanomolar affinity (pKi = 8.5), coupled with high glutamate receptor selectivity. Gavestinel displays higher than 1000-fold selectivity over NMDA, AMPA and kainate binding sites and is orally bioavailable and active in vivo. GV 150526A inhibited convulsions induced by NMDA in mice, when administered by both IV and po routes (ED50 = 0.06 and 6 mg/kg, respectively). The safety and efficacy of GV150526 were studied in two phase III randomized placebo-controlled clinical trials of acute ischemic stroke patients within 6 h from onset [The Glycine Antagonist in Neuroprotection (GAIN) International and GAIN Americas Trials] sponsored by GlaxoSmithKline. The results of these trials suggested that gavestinel was not of substantial benefit or harm to patients with primary intracerebral hemorrhage.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Glutamate [NMDA] receptor 125 Target ID: CHEMBL2094124 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16340185	Antagonist 2778
Glutamate [NMDA] receptor 125 Target ID: CHEMBL2094124 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9384243	Antagonist 2778		8.5 null [pKi]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute ischemic stroke 19 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16340185	Primary		Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
135 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10805066	400 mg 2 times / day steady-state, intravenous dose: 400 mg route of administration: Intravenous experiment type: STEADY-STATE co-administered:		GV 150526A plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
55.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10805066	400 mg 2 times / day steady-state, intravenous dose: 400 mg route of administration: Intravenous experiment type: STEADY-STATE co-administered:		GV 150526A plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
3.6% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10805066	400 mg 2 times / day steady-state, intravenous dose: 400 mg route of administration: Intravenous experiment type: STEADY-STATE co-administered:		GV 150526A plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
activator 80 substrate 1737 inhibitor 1587	substrate 1037	substrate 1217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
SULT1B1 2 SULT2A1 5 BSEP 402 SULT1A3 3 SULT1A1 4 SULT1E1 3	UGT1A8/9 2 UGT2B4 249 UGT1A1 418 UGT1A6 307 OATP2B1 104 UGT1A3 422 CYP2C19 991

Drug as perpetrator

Target	Modality	Activity
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/884#sid=26753291	inconclusive [IC50 15.8489 uM]
SULT1A3 3	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/34380635/	likely
SULT1B1 2	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/34380635/ \| https://pubmed.ncbi.nlm.nih.gov/34380635/	major
SULT1A1 8	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/34380635/ \| https://pubmed.ncbi.nlm.nih.gov/34380635/	minor [IC50 10.6 uM]
SULT1E1 3	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/34380635/	minor
SULT2A1 9	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/34380635/	minor
CYP3A4 1925	activator 214 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/885#sid=26753291	no [IC50 15.8489 uM]
BSEP 403	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22961681/	yes [IC50 <10 uM]

Drug as victim

Target	Modality	Activity
UGT1A1 418	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11116752/ \| https://pubmed.ncbi.nlm.nih.gov/11055263/	major
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11055263/	no
CYP2D6 1217	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11055263/	no
UGT1A6 307	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11055263/	no
CYP2C9 1037	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11055263/	yes
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11055263/	yes
OATP2B1 104	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/32189541/	yes
UGT1A3 422	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11116752/	yes
UGT1A8/9 2	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11116752/	yes
UGT2B4 249	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11116752/	yes

PubMed

Title	Date	PubMed
Substituted indole-2-carboxylates as in vivo potent antagonists acting as the strychnine-insensitive glycine binding site.	1997 Mar 14	9083472
Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. GAIN International Investigators.	2000 Jun 3	10859040
Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial.	2001 Apr 4	11277826
Synthesis and pharmacological characterisation of a conformationally restrained series of indole-2-carboxylates as in vivo potent glycine antagonists.	2001 Oct	11718273
Gavestinel does not improve outcome after acute intracerebral hemorrhage: an analysis from the GAIN International and GAIN Americas studies.	2005 May	15831831
Effect of the Glycine Antagonist Gavestinel on cerebral infarcts in acute stroke patients, a randomized placebo-controlled trial: The GAIN MRI Substudy.	2006	16340185

Patents

Sample Use Guides

In Vivo Use Guide

Gavestinel loading dose of 800 mg plus 5 maintenance doses (200 mg every 12 hours) for 3 days.

Route of Administration: Intravenous

In Vitro Use Guide

The effect of selective antagonist GV 150526A at trychnine-insensitive glycine sites was studied by measuring how much glycine potentiated the [3H]dopamine and [3H]noradrenaline release induced by 100 uM N-methyl-D-aspartate (NMDA) from superfused striatal and hippocampal synaptosomes in a Mg2+-free buffer. GV 150526A inhibited the effect of NMDA alone and potently antagonized the effect of glycine, with Ki = 12.4 and 17.3 nM for [3H]dopamine and [3H]noradrenaline release.

Name

Type

Language

GAVESTINEL SODIUM

Common Name

English

1H-INDOLE-2-CARBOXYLIC ACID, 4,6-DICHLORO-3-((1E)-3-OXO-3-(PHENYLAMINO)-1-PROPENYL)-, MONOSODIUM SALT

Common Name

English

1H-INDOLE-2-CARBOXYLIC ACID, 4,6-DICHLORO-3-(3-OXO-3-(PHENYLAMINO)-1-PROPENYL)-, MONOSODIUM SALT, (E)-

Common Name

English

4,6-DICHLORO-3-((1E)-3-OXO-3-(PHENYLAMINO)-1-PROPENYL)-1H-INDOLE-2-CARBOXYLIC ACID SODIUM SALT

Common Name

English

GV-150526A

Code

English

1H-INDOLE-2-CARBOXYLIC ACID, 4,6-DICHLORO-3-((1E)-3-OXO-3-(PHENYLAMINO)-1-PROPEN-1-YL)-, SODIUM SALT (1:1)

Common Name

English

Code System Code Type Description

FDA UNII

80W7787JVB