Trametinib

Base Information

• Chemical Name: Trametinib
• CAS No.: 871700-17-3
• Deprecated CAS: 1204531-14-5
• Molecular Formula: C₂₆H₂₃FIN₅O₄
• Molecular Weight: 615.403
• Hs Code.: 29339900
• European Community (EC) Number: 629-899-3
• UNII: 33E86K87QN
• ChEMBL ID: CHEMBL2103875
• DSSTox Substance ID: DTXSID901007381
• Metabolomics Workbench ID: 151997
• NCI Thesaurus Code: C77908
• Nikkaji Number: J3.135.455B
• Pharos Ligand ID: T5HZJQ4ZPZ9W
• RXCUI: 1425099
• Wikidata: Q7833138
• Wikipedia: Trametinib
• Mol file: 871700-17-3.mol

Synonyms:GSK 1120212;GSK-1120212;GSK1120212;JTP 74057;JTP-74057;JTP74057;trametinib

Chemical Property of Trametinib

Chemical Property:

• Melting Point: 300-301 °C
• PKA: 14.76±0.70(Predicted)
• PSA: 110.62000
• Density: 1.743 g/cm³
• LogP: 4.66260
• Storage Temp.: -20°C
• Solubility.: Soluble in DMSO (up to 20 mg/ml)
• XLogP3: 3.4
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 6
• Rotatable Bond Count: 5
• Exact Mass: 615.07788
• Heavy Atom Count: 37
• Complexity: 1090

Purity/Quality:

99%MIN ^*data from raw suppliers

Trametinib ^*data from reagent suppliers

Safty Information:

• Safety Statements: 24/25

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Antineoplastic Agents
• Canonical SMILES: CC1=C2C(=C(N(C1=O)C)NC3=C(C=C(C=C3)I)F)C(=O)N(C(=O)N2C4=CC=CC(=C4)NC(=O)C)C5CC5
• Recent ClinicalTrials: An Investigational Immuno-therapy Study Of Nivolumab In Combination With Trametinib With Or Without Ipilimumab In Participants With Previously Treated Cancer of the Colon or Rectum That Has Spread
• Recent EU Clinical Trials: International proof of concept therapeutic Stratification trial of Molecular Anomalies in Relapsed or Refractory HEMatological malignancies in children
• Recent NIPH Clinical Trials: A roll-over study to assess long-term effect in pediatric patients treated with dabrafenib and/or trametinib.
• Description: Trametinib is an inhibitor of MEK1 and -2. It inhibits B-RAF- and C-RAF-induced phosphorylation of MEK1 (IC50s = 3.4 and 1.8 nM, respectively) and MEK2 (IC50s = 1.6 and 0.92 nM, respectively). Trametinib inhibits the growth of two human colorectal cancer cell lines expressing mutant B-RAF (IC50s = 0.48 and 0.52 nM) and seven cell lines expressing mutant K-Ras (IC50s = 2.2-174 nM) but does not inhibit the growth of wild-type COLO 320DM cells expressing both B-RAF and K-Ras (IC50 = >10,000 nM). It reduces tumor growth in HT-29 and COLO 205 mouse xenograft models when used at doses of 0.3 and 1 mg/kg per day. Trametinib (0.03 and 0.1 mg/kg per day) also decreases M. tuberculosis-induced increases in hind paw volume in a rat model of arthritis. Formulations containing trametinib, in combination with dabrafenib, have been used in the treatment of metastatic mutant B-RAFV600E melanoma.
• Uses: Used in the systematic treatment of advanced cutaneous melanoma. An EGFR kinase inhibitor. Used in the systematic treatment of advanced cutaneous melanoma. An EGFR kinase inhibitor and potent MEK inhibitor.
• Indications: MEK, also known as MAPK, is a dual specificity threonine/tyrosine kinase that is a key node in the Raf–Ras–MEK signaling pathway. Small-molecule MEK inhibitors represent the largest group of type III allosteric inhibitors that do not bind to the ATP binding pocket. As of December 2016, besides the FDA-approved MEK1/2 inhibitors trametinib (Mekinist(R), GlaxoSmithKline) and cobimetinib (Cotellic(R), Roche), over 10 MEK inhibitors are currently in clinical trials. Trametinib was approved by FDA in 2013 for the treatment of patients with either B-Raf V600E or V600K mutated metastatic melanoma. Considering the fact that MEK and Raf are different kinases along the same pathway of Ras–Raf–MEK/ERK signaling cascade, combination strategies using both MEK and B-Raf inhibitors were utilized to overcome the observed progression using single-agent trametinib, which usually occurs within 7months. FDA approved the combination of trametinib and dabrafenib for the treatment of B-Raf V600E/K mutated metastatic melanoma in January 2014 and the combination of cobimetinib and vemurafenib for the same type of indication. Although significant improvement in progression-free survival was observed using MEK/B-Raf combination strategy, the incidence of some common adverse effects, such as vomiting, diarrhea, nausea, rash, and pyrexia, also increased.
• Clinical Use: Trametinib (GSK1120212) is an oral MEK inhibitor which has demonstrated excellent results in combination therapy for BRAF-mutated melanoma and is FDA approved in combination with BRAF inhibitors for that indication. Trametinib was evaluated initially as a single agent in KRAS mutant NSCLC in comparison with docetaxel and pemetrexed. Results as a single agent were not impressive, with an ORR of only 12% in these patients.
• Drug interactions: Potentially hazardous interactions with other drugs Antipsychotics: avoid with clozapine - increased risk of agranulocytosis.

Technology Process of Trametinib

There total 5 articles about Trametinib which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 95.0%

N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino]phenyl}acetamide (871700-25-3) → trametinib (871700-17-3)

Guidance literature:

N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino]phenyl}acetamide; With sodium methylate; In tetrahydrofuran; methanol; at 20 ℃; for 4h;

With acetic acid; In tetrahydrofuran; methanol; at 20 ℃; for 0.5h;

Reference yield: 44.8%

1-(3-aminophenyl)-3-cyclopropyl-5-{(2-fluoro-4-iodophenyl)amino}-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione → trametinib (871700-17-3)

Guidance literature:

With pyridine; acetic anhydride; In chloroform; at 0 - 20 ℃; for 2h;

Reference yield:

N-(2-fluoro-4-iodophenyl)-N'-methylurea (871700-37-7) → trametinib (871700-17-3)

Guidance literature:

Multi-step reaction with 5 steps

1: carbon tetrabromide; triethylamine; triphenylphosphine / dichloromethane / 6 h / 20 °C

2: sodium ethanolate / tetrahydrofuran / 14 h / 0 - 50 °C

3: sodium ethanolate / tetrahydrofuran / 10 h / 0 - 60 °C

4: sodium dithionite / N,N-dimethyl-formamide; water / 1 h / 90 °C

5: pyridine; acetic anhydride / chloroform / 2 h / 0 - 20 °C

With pyridine; sodium dithionite; carbon tetrabromide; sodium ethanolate; acetic anhydride; triethylamine; triphenylphosphine; In tetrahydrofuran; dichloromethane; chloroform; water; N,N-dimethyl-formamide;

upstream raw materials:

N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino]phenyl}acetamide

N-(2-fluoro-4-iodophenyl)-N'-methylurea

2-fluoro-4-iodo-N-((methylimino)methylene)aniline

ethyl 2-(2-fluoro-4-iodophenylamino)-4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate

Refernces

• 1、 -. "Method for synthesizing trametinib". Paragraph 0033; 0034; 0037; 0041; 0045. . Retrieved 2019/02/25.
• 2、 -. "5-AMINO-2,4,7-TRIOXO-3,4,7,8-TETRAHYDRO-2H-PYRIDO’2,3-D! PYRIMIDINE DERIVATIVES AND RELATED COMPOUNDS FOR THE TREATMENT OF CANCER". Page/Page column 149. . Retrieved 2008/06/13.