MAVOGLURANT

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C19H23NO3
Molecular Weight	313.3908
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]12CCC[C@@](O)(C#CC3=CC(C)=CC=C3)[C@]1([H])CCN2C(=O)OC

InChI

InChIKey=ZFPZEYHRWGMJCV-ZHALLVOQSA-N

InChI=1S/C19H23NO3/c1-14-5-3-6-15(13-14)8-11-19(22)10-4-7-17-16(19)9-12-20(17)18(21)23-2/h3,5-6,13,16-17,22H,4,7,9-10,12H2,1-2H3/t16-,17-,19-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.fraxa.org/novartis-discontinues-development-mavoglurant-afq056-fragile-x-syndrome/ | https://clinicaltrials.gov/ct2/show/NCT03242928 | https://www.ncbi.nlm.nih.gov/pubmed/25316499

Mavoglurant (AFQ056) was developed as a new metabotropic glutamate receptor 5 (mGluR5) antagonist. The efficacy of mavoglurant in humans has been assessed in L-dopa induced dyskinesia in Parkinson's disease and Fragile X syndrome in proof of principle clinical studies. However, Novartis had announced that the company would be discontinuing its development program in Fragile X following negative results in a large international clinical trial in adults, and more recently in a trial in adolescents. In both placebo-controlled trials, patients taking mavoglurant did not show improvement over placebo in any outcome measures. In patients with L-Dopa-induced dyskinesias studies failed to meet the primary objective of demonstrating improvement of dyskinesia. Mavoglurant was also investigated in phase II clinical trials to reduce chorea in Huntington's disease, but the target result was not achieved. Currently Novartis is conducting a phase II clinical trial to demonstrate whether or not this drug can benificially reduce cocaine use in Cocaine Use Disorder.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Metabotropic glutamate receptor 5 39 Target ID: P41594 Gene ID: 2915.0 Gene Symbol: GRM5 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/25316499	Antagonist 2778		30.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Fragile X syndrome 7 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26855682	Primary	Phase III 656	Unknown Approved Use Unknown
L-Dopa-induced dyskinesias 1 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27214258	Primary	Phase II 1132	Unknown Approved Use Unknown
Cocaine addiction 28 Sources: https://clinicaltrials.gov/ct2/show/NCT03242928	Primary	Phase II 1132	Unknown Approved Use Unknown
Huntington's disease 24 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25689146	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
447 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23775850	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:		MAVOGLURANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
832 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27823869	50 mg single, intravenous dose: 50 mg route of administration: Intravenous experiment type: SINGLE co-administered:		MAVOGLURANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
6292 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23775850	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:		MAVOGLURANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1760 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27823869	50 mg single, intravenous dose: 50 mg route of administration: Intravenous experiment type: SINGLE co-administered:		MAVOGLURANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
12 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23775850	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:		MAVOGLURANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
9.11 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27823869	50 mg single, intravenous dose: 50 mg route of administration: Intravenous experiment type: SINGLE co-administered:		MAVOGLURANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
400 mg single, oral Highest studied dose Dose: 400 mg Route: oral Route: single Dose: 400 mg Sources: https://pubmed.ncbi.nlm.nih.gov/28337838	unhealthy, ADULT n = 11 Health Status: unhealthy Condition: gastroesophageal reflux disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 11 Sources: https://pubmed.ncbi.nlm.nih.gov/28337838	Sources: https://pubmed.ncbi.nlm.nih.gov/28337838
50 mg single, intravenous Highest studied dose Dose: 50 mg Route: intravenous Route: single Dose: 50 mg Sources: https://pubmed.ncbi.nlm.nih.gov/27823869 Page: p.2593	healthy, ADULT n = 12 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/27823869 Page: p.2593	Disc. AE: Sinoatrial block... AEs leading to discontinuation/dose reduction: Sinoatrial block (8.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/27823869 Page: p.2593
150 mg 2 times / day multiple, oral (max) Studied dose Dose: 150 mg, 2 times / day Route: oral Route: multiple Dose: 150 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25689146 Page: p.3	unhealthy, ADULT n = 21 Health Status: unhealthy Condition: Huntington's disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 21 Sources: https://pubmed.ncbi.nlm.nih.gov/25689146 Page: p.3	Disc. AE: Disorientation... AEs leading to discontinuation/dose reduction: Disorientation (4.8%) Sources: https://pubmed.ncbi.nlm.nih.gov/25689146 Page: p.3

AEs

AE	Significance	Dose	Population
Sinoatrial block	8.3% Disc. AE	50 mg single, intravenous Highest studied dose Dose: 50 mg Route: intravenous Route: single Dose: 50 mg Sources: https://pubmed.ncbi.nlm.nih.gov/27823869 Page: p.2593	healthy, ADULT n = 12 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/27823869 Page: p.2593
Disorientation	4.8% Disc. AE	150 mg 2 times / day multiple, oral (max) Studied dose Dose: 150 mg, 2 times / day Route: oral Route: multiple Dose: 150 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25689146 Page: p.3	unhealthy, ADULT n = 21 Health Status: unhealthy Condition: Huntington's disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 21 Sources: https://pubmed.ncbi.nlm.nih.gov/25689146 Page: p.3

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	substrate 1037	substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP2C8 693 CYP1A2 1054 CYP2C19 991 CYP1A1 349 HLM 31

Drug as victim

Target	Modality	Activity
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23775850/	major
CYP1A1 349	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23775850/	minor
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23775850/	minor
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23775850/	minor
CYP2C8 693	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23775850/	minor
CYP2C9 1037	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23775850/	minor
CYP2D6 1217	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23775850/	minor
HLM 31	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23775850/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/27823869/

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P00DBPK	https://www.1pchem.com/search?query=1P00DBPK
BLD Pharm	BD239369	http://www.bldpharm.com/search/Search.html?keyword=BD239369
Chem Scene	CS-5245	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-5245
Chem Scene	CS-6126	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-6126
Excenen	EX-A1564	http://www.excenen.com/searchresultlist.php?id=EX-A1564
Lab Network	LN01346029	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01346029
MedChem Express	HY-15257	https://www.medchemexpress.com/search.html?q=HY-15257A&ft=&fa=&fp=
MedChem Express	HY-15257A	https://www.medchemexpress.com/search.html?q=HY-15257A&ft=&fa=&fp=
MolPort	MolPort-035-868-931	https://www.molport.com/shop/molecule-link/MolPort-035-868-931
MolPort	MolPort-046-418-196	https://www.molport.com/shop/molecule-link/MolPort-046-418-196
MuseChem	I003998	https://www.musechem.com/product/I003998.html
ShangHai Biochempartner	BCP20624	http://www.biochempartner.com/search_BCP20624
eMolecules	114312670	https://orderbb.emolecules.com/search/#?query=114312670
eMolecules	43611930	https://orderbb.emolecules.com/search/#?query=43611930
mcule	MCULE-4812601187	https://mcule.com/MCULE-4812601187/

PubMed

Title	Date	PubMed

Patents

Sample Use Guides

In Vivo Use Guide

l-Dopa-induced dyskinesias: mavoglurant (AFQ056) was up-titrated over two weeks from 25 mg twice daily (bid) to 100 mg bid (L-dopa kept stable), followed by three weeks during which the daily L-dopa dosage was increased by up to 300 mg/day. The study was a randomized, placebo- and active-controlled, 4-period, crossover, conduct of thorough QTc (TQT) study composed of 2 sequential phases. In the pilot phase, the safety and tolerability profile of 10-minute infusions of 25, 37.5, and 50 mg of mavoglurant was assessed in 36 healthy individuals. In the TQT phase, individuals received in random sequence single intravenous doses of mavoglurant (25 and 50 mg) and placebo and an oral dose of moxifloxacin (400 mg).

Route of Administration: Other

In Vitro Use Guide

AFQ056/mavoglurant was identified by chemical derivatization of a lead compound discovered in a HTS campaign. In vitro, AFQ056/mavoglurant had an IC50 of 30 nM in a functional assay with human mGluR5 and was selective over the other mGluR subtypes, iGluRs and a panel of 238 CNS relevant receptors, transporter or enzymes.

Name

Type

Language

MAVOGLURANT

Official Name

English

1H-INDOLE-1-CARBOXYLIC ACID, OCTAHYDRO-4-HYDROXY-4-((3-METHYLPHENYL)ETHYNYL)-, METHYL ESTER, (3AR,4S,7AR)-

Common Name

English

Methyl (3aR,4S,7aR)-4-hydroxy-4-[2-(3-methylphenyl)ethynyl]octahydro-1H-indole-1-carboxylate

Common Name

English

Mavoglurant [WHO-DD]

Common Name

English

(-)-(3AR,4S,7AR)-4-HYDROXY-4-M-TOLYLETHYNYL-OCTAHYDRO-INDOLE-1-CARBOXYLIC ACID METHYL ESTER

Systematic Name

English

AFQ-056

Code

English

1H-INDOLE-1-CARBOXYLIC ACID, OCTAHYDRO-4-HYDROXY-4-(2-(3-METHYLPHENYL)ETHYNYL)-, METHYL ESTER, (3AR,4S,7AR)-

Common Name

English

MAVOGLURANT [USAN]

Common Name

English

mavoglurant [INN]

Common Name

English

AFQ056

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

353611