| Stereochemistry | ACHIRAL |
| Molecular Formula | C31H33FN6O3.ClH |
| Molecular Weight | 593.091 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
Cl.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=JHEYROZAEFXENN-UHFFFAOYSA-N
InChI=1S/C31H33FN6O3.ClH/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);1H
| Molecular Formula | ClH |
| Molecular Weight | 36.461 |
| Charge | 0 |
| Count |
MOL RATIO
1 MOL RATIO (average) |
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
| Molecular Formula | C31H33FN6O3 |
| Molecular Weight | 556.6305 |
| Charge | 0 |
| Count |
MOL RATIO
1 MOL RATIO (average) |
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
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.
Originator
Approval Year
Sourcing
PubMed
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.
