1206799-15-6

Basic information

• Product Name: LY2801653
• Synonyms: LY2801653;N-(3-fluoro-4-((1-Methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)phenyl)-1-(4-fluorophenyl)-6-Methyl-2-oxo-1,2-dihydropyridine-3-carboxaMide;N-[3-Fluoro-4-[[1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yl]oxy]phenyl]-1-(4-fluorophenyl)-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarboxamide;Merestinib;LY2801653(Merestinib);N-(3-Fluoro-4-((1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)phenyl)-1-(4-fluorophenyl)-6-;Merestinib(LY 2801653);N-[3-fluoro-4-[1-methyl-6-(1h-pyrazol-4-yl)indazol-5-yl]oxyphenyl]-1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxamide
• CAS NO: 1206799-15-6
• Molecular Formula: C₃₀H₂₂F₂N₆O₃
• Molecular Weight: 552.5308864
• EINECS: -0
• Mol File: 1206799-15-6.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 795.3±60.0 °C(Predicted)
• Appearance: /
• Density: 1.42±0.1 g/cm3(Predicted)
• Solubility: ≥27.65 mg/mL in DMSO; insoluble in H2O; ≥5.02 mg/mL in EtOH with gentle warming and ultrasonic
• PKA: 10.83±0.70(Predicted)
• CAS DataBase Reference: LY2801653(CAS DataBase Reference)
• NIST Chemistry Reference: LY2801653(1206799-15-6)
• EPA Substance Registry System: LY2801653(1206799-15-6)

Safety Data

• Hazardous Substances Data: 1206799-15-6(Hazardous Substances Data)

Usage

Description

Different sources of media describe the Description of 1206799-15-6 differently. You can refer to the following data:
1. MET is a tyrosine kinase that leads to downstream activation of several pathways including RAS and MAPK.?As a result, it is quite possible that MET inhibition can be active in RAS mutant tumors and maybe associated with EGFR resistance in NSCLC.?Two MET inhibitors, tivantinib and onartuzumab, have been examined in KRAS mutant NSCLC with others in clinical trials at this time.
2. LY2801653 is an orally bioavailable MET kinase inhibitor (Ki = 2 nM). It also inhibits MST1R, Axl, MNK1/2, FLT3, DDR1, and DDR2 (IC50s = 11, 2, 7, 7, 0.1, and 7 nM, respectively, in a cell-based assay). It inhibits MET autophosphorylation stimulated by hepatocyte growth factor (HGF) in H460 and S114 cells (IC50s = 35.2 and 59.2 nM, respectively) and inhibits growth of Ba/F3 cells transfected with MET-activating mutations (IC50s = 12-248 nM). LY2801653 (0.01-10 μM) completely blocks cell scattering induced by HGF in DU145 cells. It reduces tumor growth in MET autocrine (U-87MG) and MET over-expression (H441) mouse xenograft models when administered at doses of 4 and 12 mg/kg.

Clinical Use

Preclinical testing also has shown merestinib to inhibit several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, and NTRK1/2/3.

references

[1] yan s b et al. , ly2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against met, mst1r, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. invest new drugs. 2012, 31: 833-844.

Upstream product

• 1206800-28-3 6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole 
• 1206800-27-2 6-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-5-ol 
• 1735-88-2 2-cyano-N-[4-(fluoro)phenyl]acetamide 
• 1206800-25-0 2,4-dibromo-5-(2-fluoro-4-nitrophenoxy) benzaldehyde 
• 1206800-18-1 6-bromo-1H-indazol-5-ol 
• 1206800-17-0 6-bromo-5-methoxy-1H-indazole 
• 1206800-26-1 1-(2,4-dibromo-5-(2-fluoro-4-nitrophenoxy)benzylidene)-2-methylhydrazine 
• 1577180-04-1 C₉H₁₀Br₂N₂O 
• 861084-04-0 5-bromo-4-methoxy-2-methylbenzenamine 
• 371-40-4 4-fluoroaniline 
• 31601-41-9 N-(4-methoxy-2-methylphenyl)acetamide 
• 1206800-24-9 6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole 
• 102-50-1 2-methyl-4-methoxyaniline 
• 1577180-07-4 N-(4-((6-bromo-1-methyl-1H-indazol-5-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 

Relevant articles and documents

Small-Volume Continuous Manufacturing of Merestinib. Part 2. Technology Transfer and cGMP Manufacturing

Technology transfer of a small volume continuous (SVC) process and Current Good Manufacturing Practices (cGMP) manufacturing of merestinib are described. A hybrid batch-SVC campaign was completed at a contract manufacturing organization under cGMP. The decision process by which unit operations were selected for implementation in flow for the cGMP campaign is discussed. The hybrid process comprised a Suzuki-Miyaura cross-coupling reaction, a nitro-group hydrogenolysis, a continuous amide bond formation, and a continuous deprotection. A continuous crystallization using two mixed suspension, mixed product removal (MSMPR) crystallizers and a filtration with in situ dissolution were employed for purification between the two SVC steps. Impurity levels were monitored using both online process analytical technology (PAT) and offline measurements. The continuous processing steps operated uninterrupted for 18 days to yield the drug substance in solution at a throughput of 12.5 kg/day. Crystallization in batch mode afforded 183 kg of the drug substance in specification. Success of the campaign was attributed to robustness of the control strategy and to the multiyear partnership in continuous manufacturing between the development organization and the contract manufacturer. Key learnings are offered from the perspectives of both the development organization and the contract manufacturer.

Route design and development of a MET kinase inhibitor: A copper-catalyzed preparation of an N 1 - Methylindazole

The synthesis of a MET kinase inhibitor in an overall yield of 22% was achieved over eight steps starting with 3-hydroxybenzaldehyde, an improvement from the initial 12-step process with a 5.4% yield. Highlights of the process chemistry design and development are a Cu-catalyzed cyclization to form an important N1-methylindazole ring, a selective nitro reduction in the presence of an aryl bromide, a late-stage Suzuki cross-coupling, and a base-promoted Boc deprotection to form the desired drug candidate.