TIRASEMTIV

Details

Stereochemistry	ACHIRAL
Molecular Formula	C12H14N4O
Molecular Weight	230.2658
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCC(CC)N1C(=O)NC2=NC=C(N=C12)C#C

InChI

InChIKey=RSQGZEAXODVTOL-UHFFFAOYSA-N

InChI=1S/C12H14N4O/c1-4-8-7-13-10-11(14-8)16(12(17)15-10)9(5-2)6-3/h1,7,9H,5-6H2,2-3H3,(H,13,15,17)

HIDE SMILES / InChI

Molecular Formula	C12H14N4O
Molecular Weight	230.2658
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/22344294
Curator's Comment: Description was created using several sources including: http://www.als.net/news/pivotal-study-for-tirasemtiv-opens-for-enrollment/

Tirasemtiv is a fast skeletal troponin activator and is a candidate amyotrophic lateral sclerosis (AML) therapeutic. It is a small molecule that enhances the signals between motor neurons and neuromuscular junctions. Tirasemtiv increases muscle strength by amplifying the response of muscle when neuromuscular input is diminished secondary to a neuromuscular disease. Tirasemtiv selectively binds to the fast skeletal troponin complex, thus slowing down the rate of calcium release from troponin C and sensitizing muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards as does the force-frequency relationship of a nerve-muscle pair.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Troponin I, fast skeletal muscle 1 Target ID: P48788 Gene ID: 7136.0 Gene Symbol: TNNI2 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/22344294	Activator 1430		40.0 nM [Kd]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Amyotrophic lateral sclerosis 41 Sources: https://clinicaltrials.gov/ct2/show/NCT02496767	Primary		Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
18.3 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24872402	750 mg single, oral dose: 750 mg route of administration: Oral experiment type: SINGLE co-administered:		TIRASEMTIV plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
11.271 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22591195	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:		TIRASEMTIV plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
238.2 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/24872402	750 mg single, oral dose: 750 mg route of administration: Oral experiment type: SINGLE co-administered:		TIRASEMTIV plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
175.881 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22591195	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:		TIRASEMTIV plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
750 mg single, oral Highest studied dose Dose: 750 mg Route: oral Route: single Dose: 750 mg Sources: https://pubmed.ncbi.nlm.nih.gov/24872402 Page: p.303	unhealthy, ADULT n = 33 Health Status: unhealthy Condition: peripheral artery disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 33 Sources: https://pubmed.ncbi.nlm.nih.gov/24872402 Page: p.303	Disc. AE: Dizziness... AEs leading to discontinuation/dose reduction: Dizziness (grade 3, 6%) Sources: https://pubmed.ncbi.nlm.nih.gov/24872402 Page: p.303
250 mg 2 times / day multiple, oral Studied dose Dose: 250 mg, 2 times / day Route: oral Route: multiple Dose: 250 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/23952636 Page: p.577	unhealthy, ADULT n = 16 Health Status: unhealthy Condition: amyotrophic lateral sclerosis Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/23952636 Page: p.577	Disc. AE: Confusion, Ataxia... AEs leading to discontinuation/dose reduction: Confusion (6.25%) Ataxia (6.25%) Sources: https://pubmed.ncbi.nlm.nih.gov/23952636 Page: p.577
250 mg 2 times / day multiple, oral (max) Studied dose Dose: 250 mg, 2 times / day Route: oral Route: multiple Dose: 250 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/29402141 Page: p.6	unhealthy, ADULT n = 744 Health Status: unhealthy Condition: amyotrophic lateral sclerosis Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 744 Sources: https://pubmed.ncbi.nlm.nih.gov/29402141 Page: p.6	Disc. AE: Nausea, Dizziness... AEs leading to discontinuation/dose reduction: Nausea (4.2%) Dizziness (10.3%) Fatigue (7.4%) Sources: https://pubmed.ncbi.nlm.nih.gov/29402141 Page: p.6
375 mg 1 times / day multiple, oral Studied dose Dose: 375 mg, 1 times / day Route: oral Route: multiple Dose: 375 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/23952636 Page: p.577	unhealthy, ADULT n = 18 Health Status: unhealthy Condition: amyotrophic lateral sclerosis Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 18 Sources: https://pubmed.ncbi.nlm.nih.gov/23952636 Page: p.577	Disc. AE: Dizziness, Mental status changes... AEs leading to discontinuation/dose reduction: Dizziness (5.6%) Mental status changes (5.6%) Sources: https://pubmed.ncbi.nlm.nih.gov/23952636 Page: p.577

AEs

AE	Significance	Dose	Population
Dizziness	grade 3, 6% Disc. AE	750 mg single, oral Highest studied dose Dose: 750 mg Route: oral Route: single Dose: 750 mg Sources: https://pubmed.ncbi.nlm.nih.gov/24872402 Page: p.303	unhealthy, ADULT n = 33 Health Status: unhealthy Condition: peripheral artery disease Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 33 Sources: https://pubmed.ncbi.nlm.nih.gov/24872402 Page: p.303
Ataxia	6.25% Disc. AE	250 mg 2 times / day multiple, oral Studied dose Dose: 250 mg, 2 times / day Route: oral Route: multiple Dose: 250 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/23952636 Page: p.577	unhealthy, ADULT n = 16 Health Status: unhealthy Condition: amyotrophic lateral sclerosis Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/23952636 Page: p.577
Confusion	6.25% Disc. AE	250 mg 2 times / day multiple, oral Studied dose Dose: 250 mg, 2 times / day Route: oral Route: multiple Dose: 250 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/23952636 Page: p.577	unhealthy, ADULT n = 16 Health Status: unhealthy Condition: amyotrophic lateral sclerosis Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/23952636 Page: p.577
Dizziness	10.3% Disc. AE	250 mg 2 times / day multiple, oral (max) Studied dose Dose: 250 mg, 2 times / day Route: oral Route: multiple Dose: 250 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/29402141 Page: p.6	unhealthy, ADULT n = 744 Health Status: unhealthy Condition: amyotrophic lateral sclerosis Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 744 Sources: https://pubmed.ncbi.nlm.nih.gov/29402141 Page: p.6
Nausea	4.2% Disc. AE	250 mg 2 times / day multiple, oral (max) Studied dose Dose: 250 mg, 2 times / day Route: oral Route: multiple Dose: 250 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/29402141 Page: p.6	unhealthy, ADULT n = 744 Health Status: unhealthy Condition: amyotrophic lateral sclerosis Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 744 Sources: https://pubmed.ncbi.nlm.nih.gov/29402141 Page: p.6
Fatigue	7.4% Disc. AE	250 mg 2 times / day multiple, oral (max) Studied dose Dose: 250 mg, 2 times / day Route: oral Route: multiple Dose: 250 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/29402141 Page: p.6	unhealthy, ADULT n = 744 Health Status: unhealthy Condition: amyotrophic lateral sclerosis Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 744 Sources: https://pubmed.ncbi.nlm.nih.gov/29402141 Page: p.6
Dizziness	5.6% Disc. AE	375 mg 1 times / day multiple, oral Studied dose Dose: 375 mg, 1 times / day Route: oral Route: multiple Dose: 375 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/23952636 Page: p.577	unhealthy, ADULT n = 18 Health Status: unhealthy Condition: amyotrophic lateral sclerosis Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 18 Sources: https://pubmed.ncbi.nlm.nih.gov/23952636 Page: p.577
Mental status changes	5.6% Disc. AE	375 mg 1 times / day multiple, oral Studied dose Dose: 375 mg, 1 times / day Route: oral Route: multiple Dose: 375 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/23952636 Page: p.577	unhealthy, ADULT n = 18 Health Status: unhealthy Condition: amyotrophic lateral sclerosis Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 18 Sources: https://pubmed.ncbi.nlm.nih.gov/23952636 Page: p.577

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY34024	https://www.001chemical.com/chem/search?q=DY34024
1PlusChem LLC	1P003BB2	https://www.1pchem.com/search?query=1P003BB2
A2B Chem	AB53822	http://a2bchem.com/prod/AB53822
AChemBlock	O33820	http://www.achemblock.com/catalogsearch/result/?q=O33820
AOBIOUS INC	AOB87719	http://aobious.com/aobious/search?search_query=AOB87719
Angene	AGN-PC-0WH98S	http://www.angenechemical.com/productshow/AGN-PC-0WH98S.html
AstaTech	41312	http://astatechinc.com/CPSResult.php?CRNO=41312
BLD Pharm	BD305445	http://www.bldpharm.com/search/Search.html?keyword=BD305445
Chem Scene	CS-2783	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-2783
ChemShuttle	105460	https://www.chemshuttle.com/catalogsearch/result/?q=105460
Combi-Blocks	QJ-6210	http://www.combi-blocks.com/cgi-bin/find.cgi?QJ-6210
Debye Scientific	DA-48425	https://www.debyesci.com/index.php?id=product&ext[cno]=DA-48425
Excenen	EX-A367	http://www.excenen.com/searchresultlist.php?id=EX-A367
Fluorochem	468354	http://www.fluorochem.co.uk/Products/Product?code=468354
Lab Network	LN01301597	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01301597
Matrix Scientific	131757	http://www.matrixscientific.com/131757.html
MedChem Express	HY-15964	https://www.medchemexpress.com/search.html?q=HY-15964&ft=&fa=&fp=
MolPort	MolPort-039-331-984	https://www.molport.com/shop/molecule-link/MolPort-039-331-984
Molcore	MC34024	http://www.molcore.com/CatMC34024.html
ShangHai Biochempartner	BCP27991	http://www.biochempartner.com/search_BCP27991
eMolecules	49274536	https://orderbb.emolecules.com/search/#?query=49274536
eMolecules	50282263	https://orderbb.emolecules.com/search/#?query=50282263
eNovation Chemicals	D372418	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D372418&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-8173869585	https://mcule.com/MCULE-8173869585/

PubMed

Title	Date	PubMed
Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases.	2012 Feb 19	22344294
A study to evaluate safety and tolerability of repeated doses of tirasemtiv in patients with amyotrophic lateral sclerosis.	2013 Dec	23952636
Effect of tirasemtiv, a selective activator of the fast skeletal muscle troponin complex, in patients with peripheral artery disease.	2014 Aug	24872402
Tirasemtiv amplifies skeletal muscle response to nerve activation in humans.	2014 Dec	24634285

Patents

Sample Use Guides

In Vivo Use Guide

Day 1 through week 48 - 125 mg of tirasemtiv twice a day (Experimental Group 2); day 1 through week 2 - 125 mg of tirasemtiv twice a day, weeks 3 through 48 - 125 mg in AM and 250 mg in PM (Experimental Group 3) and weeks 3 and 4 - 125 mg in AM and 250 mg in PM. weeks 5 through 48 - 500 mg in AM and 500 mg in PM.

Route of Administration: Oral

In Vitro Use Guide

Addition of 5.0 uM CK-2017357 (tirasemtiv) to fast skeletal myofibrils resulted in a leftward shift in the calcium-dependent myosin adenosine triphosphatase (ATPase) relationship with the pCa50 shifting from 5.61 ± 0.01 (control) to 6.52 ± 0.02 (CK-2017357, 5.0 uM). An increase in the ATPase rate at a fixed calcium concentration resulted in CK-2017357 EC50 of 390 ± 17 nM for fast skeletal muscle, with little or no effect in myofibrils from slow skeletal and cardiac muscle demonstrating that CK-2017357 is a selective calcium sensitizer of the fast skeletal troponin complex.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 01:41:13 GMT 2023` Edited by `admin` on `Sat Dec 16 01:41:13 GMT 2023`
Record UNII	G8WSM7R635
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TIRASEMTIV

Official Name

English

tirasemtiv [INN]

Common Name

English

2H-IMIDAZO(4,5-B)PYRAZIN-2-ONE, 1-(1-ETHYLPROPYL)-6-ETHYNYL-1,3-DIHYDRO-

Systematic Name

English

TIRASEMTIV [USAN]

Common Name

English

CK2017357

Code

English

CK-2017357

Code

English

Tirasemtiv [WHO-DD]

Common Name

English

6-ETHYNYL-1-(PENTAN-3-YL)-2H-IMIDAZO(4,5-B)PYRAZIN-2-ONE

Systematic Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

301710