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Details

Stereochemistry ACHIRAL
Molecular Formula C31H33FN6O3
Molecular Weight 556.6305
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of PEXMETINIB

SMILES

CC1=CC=C(C=C1)N2N=C(C=C2NC(=O)NCC3=CC(F)=CC=C3OC4=CC5=C(C=C4)N(CCO)N=C5)C(C)(C)C

InChI

InChIKey=LNMRSSIMGCDUTP-UHFFFAOYSA-N
InChI=1S/C31H33FN6O3/c1-20-5-8-24(9-6-20)38-29(17-28(36-38)31(2,3)4)35-30(40)33-18-22-15-23(32)7-12-27(22)41-25-10-11-26-21(16-25)19-34-37(26)13-14-39/h5-12,15-17,19,39H,13-14,18H2,1-4H3,(H2,33,35,40)

HIDE SMILES / InChI

Description
Curator's Comment: The description was created based on several sources, including https://clinicaltrials.gov/ct2/show/NCT00916227 | https://clinicaltrials.gov/ct2/show/NCT01496495 | https://www.ncbi.nlm.nih.gov/pubmed/25480830 | https://www.ncbi.nlm.nih.gov/pubmed/27287719

Pexmetinib (ARRY-614) is a potent, orally bioavailable, dual p38 MAPK/Tie-2 inhibitor with potential antineoplastic, anti-inflammatory and antiangiogenic activities. Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases and abrogated the effects of TNF-alpha on healthy hematopoietic stem cells. In ex vivo stimulated human whole blood, LPS-induced cytokines was inhibited by Pexmetinib with an IC50 value ranging from 50-120 nM. ARRY-614 inhibited the release of IL-6 from SEA- or LPS-challenged mice with an ED50 value less than 10 mg/kg. Combining Pexmetinib with lenalidomide inhibited both pro-inflammatory cytokines and tumor growth in vivo with higher potency, compared with either agent alone. In dose escalation or expansion cohorts, treatment with Pexmetinib either once daily or twice daily was applied to forty-five patients. Pexmetinib reduced the levels of circulating biomarkers and the p38 MAPK activation of bone marrow.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
1.0 nM [IC50]
4.0 nM [IC50]
26.0 nM [IC50]
35.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
PubMed

PubMed

TitleDatePubMed
An exploratory, randomized, parallel-group, open-label, relative bioavailability study with an additional two-period crossover food-effect study exploring the pharmacokinetics of two novel formulations of pexmetinib (ARRY-614).
2015
Patents

Sample Use Guides

1,200 mg once daily as the optimal dose for further study.
Route of Administration: Oral
Human umbilical vein endothelial cells (HUVEC) and HEK-293 human embryonic kidney cells (ATCC) engineered to express constitutively active Tie2 (HEK-Tie2) were used to assess p38 and Tie2 phosphorylation in vitro. HEK-Tie2 cells were treated with 1 mg/mL doxycycline 24 hours prior to drug treatment to induce Tie2 expression, and HUVECs were pretreated for 1 hour with 1 mkg/mL anisomycin or 0.1 mkg/mL recombinant angpt-1 (R&D Systems #923-AN- 025) to activate p38 or Tie2, respectively. Cells were treated with varying concentrations of pexmetinib for 2 hours (0.25% BSA, 0.2% DMSO), lysed in RIPA buffer then subjected to Western blot analysis.
Name Type Language
PEXMETINIB
INN   WHO-DD  
INN  
Official Name English
ARRY-614
Code English
Pexmetinib [WHO-DD]
Common Name English
pexmetinib [INN]
Common Name English
N-(3-TERT-BUTYL-1-P-TOLYL-1H-PYRAZOL-5-YL)-N'-(5-FLUORO-2-(1-(2-HYDROXYETHYL)-1H-INDAZOL-5-YLOXY)BENZYL)UREA
Systematic Name English
UREA, N-(3-(1,1-DIMETHYLETHYL)-1-(4-METHYLPHENYL)-1H-PYRAZOL-5-YL)-N'-((5-FLUORO-2-((1-(2-HYDROXYETHYL)-1H-INDAZOL-5-YL)OXY)PHENYL)METHYL)-
Systematic Name English
Classification Tree Code System Code
NCI_THESAURUS C129825
Created by admin on Sat Dec 16 09:46:40 GMT 2023 , Edited by admin on Sat Dec 16 09:46:40 GMT 2023
NCI_THESAURUS C1404
Created by admin on Sat Dec 16 09:46:40 GMT 2023 , Edited by admin on Sat Dec 16 09:46:40 GMT 2023
NCI_THESAURUS C1742
Created by admin on Sat Dec 16 09:46:40 GMT 2023 , Edited by admin on Sat Dec 16 09:46:40 GMT 2023
Code System Code Type Description
SMS_ID
300000034271
Created by admin on Sat Dec 16 09:46:40 GMT 2023 , Edited by admin on Sat Dec 16 09:46:40 GMT 2023
PRIMARY
CAS
945614-12-0
Created by admin on Sat Dec 16 09:46:40 GMT 2023 , Edited by admin on Sat Dec 16 09:46:40 GMT 2023
PRIMARY
PUBCHEM
24765037
Created by admin on Sat Dec 16 09:46:40 GMT 2023 , Edited by admin on Sat Dec 16 09:46:40 GMT 2023
PRIMARY
INN
9859
Created by admin on Sat Dec 16 09:46:40 GMT 2023 , Edited by admin on Sat Dec 16 09:46:40 GMT 2023
PRIMARY
FDA UNII
3750D0U8B5
Created by admin on Sat Dec 16 09:46:40 GMT 2023 , Edited by admin on Sat Dec 16 09:46:40 GMT 2023
PRIMARY
ChEMBL
CHEMBL3545297
Created by admin on Sat Dec 16 09:46:40 GMT 2023 , Edited by admin on Sat Dec 16 09:46:40 GMT 2023
PRIMARY
NCI_THESAURUS
C85481
Created by admin on Sat Dec 16 09:46:40 GMT 2023 , Edited by admin on Sat Dec 16 09:46:40 GMT 2023
PRIMARY