RALIMETINIB MESYLATE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C24H29FN6.2CH4O3S
Molecular Weight	612.737
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CS(O)(=O)=O.CS(O)(=O)=O.CC(C)(C)CN1C(N)=NC2=CC=C(N=C12)C3=C(NC(=N3)C(C)(C)C)C4=CC=C(F)C=C4

InChI

InChIKey=NARMJPIBAXVUIE-UHFFFAOYSA-N

InChI=1S/C24H29FN6.2CH4O3S/c1-23(2,3)13-31-20-17(28-22(31)26)12-11-16(27-20)19-18(14-7-9-15(25)10-8-14)29-21(30-19)24(4,5)6;2*1-5(2,3)4/h7-12H,13H2,1-6H3,(H2,26,28)(H,29,30);2*1H3,(H,2,3,4)

HIDE SMILES / InChI

Description
Sources: http://adisinsight.springer.com/drugs/800034528
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/24356814

Ralimetinib (LY2228820), a trisubstituted imidazole derivative, is a potent and selective, ATP-competitive inhibitor of the α- and β-isoforms of p38 mitogen-activated protein kinase. LY2228820 produced significant tumor growth delay in multiple in vivo cancer models (melanoma, non-small cell lung cancer, ovarian, glioma, myeloma, breast). Eli Lilly is developing ralimetinib for the treatment of cancer.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
MAP kinase p38 alpha 35 Target ID: CHEMBL260 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24356814	Inhibitor 8297		5.3 nM [IC50]
MAP kinase p38 beta 11 Target ID: CHEMBL3961 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24356814	Inhibitor 8297		3.2 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Glioblastoma 65 Sources: http://adisinsight.springer.com/drugs/800034528	Primary	Phase II 1132	Unknown Approved Use Unknown
Ovarian cancer 157 Sources: http://adisinsight.springer.com/drugs/800034528	Primary	Phase II 1132	Unknown Approved Use Unknown
Breast cancer 434 Sources: http://adisinsight.springer.com/drugs/800034528	Primary	Phase II 1132	Unknown Approved Use Unknown
Colorectal cancer 101 Sources: http://adisinsight.springer.com/drugs/800034528	Primary	Phase I 428	Unknown Approved Use Unknown
Non-small cell lung cancer 206 Sources: http://adisinsight.springer.com/drugs/800034528	Primary	Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
1400 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26581242	300 mg 2 times / day steady-state, oral dose: 300 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RALIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2230 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26581242	420 mg 2 times / day steady-state, oral dose: 420 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RALIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3060 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26581242	560 mg 2 times / day steady-state, oral dose: 560 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RALIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
574 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26581242	160 mg 2 times / day steady-state, oral dose: 160 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RALIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
963 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26581242	200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RALIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
17900 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26581242	300 mg 2 times / day steady-state, oral dose: 300 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RALIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
26200 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26581242	420 mg 2 times / day steady-state, oral dose: 420 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RALIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
40500 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26581242	560 mg 2 times / day steady-state, oral dose: 560 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RALIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
7490 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26581242	160 mg 2 times / day steady-state, oral dose: 160 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RALIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
92.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26581242	300 mg 2 times / day steady-state, oral dose: 300 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RALIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
77.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26581242	420 mg 2 times / day steady-state, oral dose: 420 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RALIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
193 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26581242	560 mg 2 times / day steady-state, oral dose: 560 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RALIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
86.8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26581242	160 mg 2 times / day steady-state, oral dose: 160 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	RALIMETINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY116312	https://www.001chemical.com/chem/search?q=DY116312
1PlusChem LLC	1P00GUKR	https://www.1pchem.com/search?query=1P00GUKR
A2B Chem	AH85323	http://a2bchem.com/prod/AH85323
AK Scientific	2526AH	https://aksci.com/item_detail.php?cat=2526AH
AK Scientific	X7400	https://aksci.com/item_detail.php?cat=X7400
Ambeed	A413122	http://www.ambeed.com/search/Search.html?keyword=A413122
Angene	AGN-PC-00BT9J	http://www.angenechemical.com/productshow/AGN-PC-00BT9J.html
ApexBio Technology	A5566	https://www.apexbt.com/catalogsearch/result/?q=A5566
AstaTech	41536	http://astatechinc.com/CPSResult.php?CRNO=41536
Axon MedChem	1895	https://www.axonmedchem.com/product/1895
BLD Pharm	BD306011	http://www.bldpharm.com/search/Search.html?keyword=BD306011
Chem Scene	CS-0208	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0208
ChemShuttle	104779	https://www.chemshuttle.com/catalogsearch/result/?q=104779
ChemShuttle	104781	https://www.chemshuttle.com/catalogsearch/result/?q=104781
Combi-Blocks	QW-4235	http://www.combi-blocks.com/cgi-bin/find.cgi?QW-4235
Debye Scientific	DB-076584	https://www.debyesci.com/index.php?id=product&ext[cno]=DB-076584
Excenen	EX-A2289	http://www.excenen.com/searchresultlist.php?id=EX-A2289
KeyOrganics	AS-56110	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-56110
Matrix Scientific	145185	http://www.matrixscientific.com/145185.html
MedChem Express	HY-13241	https://www.medchemexpress.com/search.html?q=HY-13241&ft=&fa=&fp=
MolPort	MolPort-009-679-493	https://www.molport.com/shop/molecule-link/MolPort-009-679-493
MolPort	MolPort-016-633-222	https://www.molport.com/shop/molecule-link/MolPort-016-633-222
Molcore	MC116312	http://www.molcore.com/CatMC116312.html
Molnova	M16242	https://www.molnova.com/en/serch-list.html?keywords=M16242
MuseChem	I005171	https://www.musechem.com/product/I005171.html
MuseChem	I008970	https://www.musechem.com/product/I008970.html
ShangHai Biochempartner	BCP02033	http://www.biochempartner.com/search_BCP02033
ShangHai Biochempartner	BCP02295	http://www.biochempartner.com/search_BCP02295
Toronto Research Chemicals	L486500	https://www.trc-canada.com/product-detail/?CatNum=L486500
eMolecules	300527130	https://orderbb.emolecules.com/search/#?query=300527130
eMolecules	32278024	https://orderbb.emolecules.com/search/#?query=32278024
eMolecules	43473265	https://orderbb.emolecules.com/search/#?query=43473265
eMolecules	48668657	https://orderbb.emolecules.com/search/#?query=48668657
eMolecules	48670925	https://orderbb.emolecules.com/search/#?query=48670925
eNovation Chemicals	D395254	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D395254&searchbtn.x=0&searchbtn.y=0
eNovation Chemicals	D491462	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D491462&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-6055286759	https://mcule.com/MCULE-6055286759/
mcule	MCULE-7712354790	https://mcule.com/MCULE-7712354790/

PubMed

Title	Date	PubMed
Imidazolyl benzimidazoles and imidazo[4,5-b]pyridines as potent p38alpha MAP kinase inhibitors with excellent in vivo antiinflammatory properties.	2008 Jan 1	18039577
LY2228820 dimesylate, a selective inhibitor of p38 mitogen-activated protein kinase, reduces angiogenic endothelial cord formation in vitro and in vivo.	2013 Mar 1	23335506
Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity.	2014 Feb	24356814
P38 regulates the Wnt inhibitor Dickkopf-1 in breast cancer.	2015 Oct 30	26407843
p38 MAPK regulates the Wnt inhibitor Dickkopf-1 in osteotropic prostate cancer cells.	2016 Feb 25	26913608
A First-in-Human Phase I Study of the Oral p38 MAPK Inhibitor, Ralimetinib (LY2228820 Dimesylate), in Patients with Advanced Cancer.	2016 Mar 1	26581242

Patents

Sample Use Guides

In Vivo Use Guide

The recommended phase II dose of Ralimetinib in patients with advanced cancer was 300 mg every 12 hours as monotherapy or in combination with tamoxifen.

Route of Administration: Oral

In Vitro Use Guide

In cell-based assays, Ralimetinib (LY2228820) potently and selectively inhibited phosphorylation of MK2 (Thr334) in anisomycin-stimulated HeLa cells (at 9.8 nmol/L by Western blot analysis) and anisomycin-induced mouse RAW264.7 macrophages (IC(50) = 35.3 nmol/L) with no changes in phosphorylation of p38α MAPK, JNK, ERK1/2, c-Jun, ATF2, or c-Myc ≤ 10 μmol/L. LY2228820 also reduced TNF-α secretion by lipopolysaccharide/IFN-γ-stimulated macrophages (IC(50) = 6.3 nmol/L).

Name

Type

Language

RALIMETINIB MESYLATE

Official Name

English

RALIMETINIB MESYLATE [USAN]

Common Name

English

LSN-2322600

Code

English

Ralimetinib mesilate [WHO-DD]

Common Name

English

ZZ-84

Code

English

RALIMETINIB MESILATE

Common Name

English

5-(2-TERT-BUTYL-5-(4-FLUORO-PHENYL)-1H-IMIDAZOL-4-YL)-3-(2,2-DIMETHYL-PROPYL)-3H-IMIDAZO(4,5-B)PYRIDIN-2-YLAMINE DIMETHANESULFONATE

Systematic Name

English

LY2228820 DIMESYLATE

Code

English

3H-IMIDAZO(4,5-B)PYRIDIN-2-AMINE, 5-(2-(1,1-DIMETHYLETHYL)-4-(4-FLUOROPHENYL)-1H-IMIDAZOL-5-YL)-3-(2,2-DIMETHYLPROPYL)-, METHANESULFONATE (1:2)

Systematic Name

English

5-(2-(tert-Butyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-3-(2,2-dimethylpropyl)-3H-imidazo[4,5-b]pyridin-2-amine dimethanesulfonate

Systematic Name

English

LY-2228820 DIMESYLATE

Code

English

LSN2322600

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C61074