945614-12-0

Basic information

• Product Name: ARRY-614
• Synonyms: ARRY-614;pexmetinib,ARRY-614;N-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)-N'-[5-fluoro-2-[1-(2-hydroxyethyl)-1H-indazol-5-yloxy]benzyl]urea;1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[[5-fluoro-2-[1-(2-hydroxyethyl)indazol-5-yl]oxyphenyl]methyl]urea
• CAS NO: 945614-12-0
• Molecular Formula: C₃₁H₃₃FN₆O₃
• Molecular Weight: 556.6305232
• Mol File: 945614-12-0.mol
• Article Data: 1

Chemical Properties

• Boiling Point: 694.1±55.0 °C(Predicted)
• Appearance: /
• Density: 1.28±0.1 g/cm3(Predicted)
• Solubility: insoluble in H2O; ≥107.6 mg/mL in DMSO; ≥113 mg/mL in EtOH
• PKA: 13.00±0.46(Predicted)
• CAS DataBase Reference: ARRY-614(CAS DataBase Reference)
• NIST Chemistry Reference: ARRY-614(945614-12-0)
• EPA Substance Registry System: ARRY-614(945614-12-0)

Safety Data

• Hazardous Substances Data: 945614-12-0(Hazardous Substances Data)

Usage

Description

ARRY-614, also known as Pexmetinib, is a potent and orally bioavailable dual p38 MAPK/Tie-2 inhibitor that plays a crucial role in preventing tumor growth.

Uses

Used in Oncology:
ARRY-614 is used as an anticancer agent for its ability to inhibit the p38 MAPK and Tie-2 pathways, which are involved in tumor growth and angiogenesis. This makes it a promising candidate for the treatment of various types of cancer.
Used in Drug Development:
ARRY-614 is used as a research tool in the development of new cancer therapies, as its dual inhibition mechanism can provide insights into the potential benefits and challenges of targeting multiple pathways simultaneously in cancer treatment.
Used in Clinical Trials:
ARRY-614 is used in clinical trials to evaluate its safety, efficacy, and optimal dosing regimens for the treatment of specific cancer types, such as non-small cell lung cancer (NSCLC) and other solid tumors.

Biological Activity

pexmetinib (arry-614) is a potent inhibitor of cytokine synthesis, via the dual inhibition of p38 mitogen-activated protein kinase (mapk), and tie2/tek receptor tyrosine kinase. the in vitro ic50 values of arr y-614 for both tie2 and p38 mitogen-activated protein kinase are 1000 ng/ml and 100 ng/ml, respectively [1, 2].p38 is a group of mitogen-activated protein kinases. mapks are activated by the dual phosphorylation of tyr and thr residues in the thr-xaa-tyr motif in subdomain viii. data indicated that p38 mapk may mediate signaling to the nucleus [3].arry-614 is active against mapk and tie2/tek receptor tyrosine kinase in cells. in primary human bone marrow stromal cells, arry-614 inhibited basal cytokines with an ic50 value ranging from 50-100 nm [4].in dose escalation or expansion cohorts, treatment with arry-614 either once daily or twice daily was applied to forty-five patients. arry-614 reduced the levels of circulating biomarkers and the p38 mapk activation of bone marrow [1]. in ex vivo stimulated human whole blood, lps-induced cytokines was inhibited by arry-614 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 arry-614 with lenalidomide inhibited both pro-inflammatory cytokines and tumor growth in vivo with higher potency, compared with either agent alone [4].

references

[1]. garcia-manero g, khoury hj, jabbour e, et al. a phase i study of oral arry-614, a p38 mapk/tie2 dual inhibitor, in patients with low or intermediate-1 risk myelodysplastic syndromes. clinical cancer research, 2015, 21(5): 985-994.[2]. wollenberg la, corson dt, nugent ca, et al. 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). clinical pharmacology: advances and applications, 2015, 7: 87.[3]. raingeaud j, whitmarsh aj, barrett t, et al. mkk3-and mkk6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. molecular and cellular biology, 1996, 16(3): 1247-1255.[4]. winski s, humphries m, yeh t, et al. activity of arry-614, an inhibitor of p38 map kinase and angiogenic targets, in hematologic malignancies. cancer research, 2009, 69(9 supplement): 331-331.

Upstream product

• 945614-23-3 methyl 2-(5-(2-((3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)methyl)-4-fluorophenoxy)-1H-indazol-1-yl)acetate 
• 945614-19-7 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-((5-fluoro-2-(1-(2-oxoethyl)-1H-indazol-5-yloxy)phenyl)methyl)urea 

Downstream Products

• 1416216-01-7 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea hydrochloride 
• 945614-20-0 dibenzyl 2-(5-(2-((3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)methyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethylphosphate 
• 945614-24-4 di-tert-butyl 2-(5-(2-((3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)methyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethylphosphate 

Relevant articles and documents

KINASE INHIBITORS AND METHODS OF USE THEREOF

The compound of Formula (I) and pharmaceutically acceptable salts and prodrugs thereof are useful in the treatment and prevention of various disorders mediated by kinases.