| Identification | Back Directory | [Name]
GSK1120212 (DMSO solvate) | [CAS]
1187431-43-1 | [Synonyms]
154988
JTP-74057
GSK 1120212B
JTP-74057;GSK1120212
TraMetinib DMSO (API)
JTP-74057 (DMSO solvate)
GSK1120212 (DMSO solvate)
TraMetinib (DMSO solvate)
rametinibdimethylsulfoxide
Trametinib dimethyl sulfoxide
GSK-1120212 dimethyl sulfoxide
Trametinib DMSO solvate, >=98%
N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-1H,2H,3H,4H,6H,7H-pyrido[4,3-d]pyrimidin-1-yl}phenyl)acetamide
N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide compound with (methylsulfinyl)methane (1:1) | [Molecular Formula]
C28H29FIN5O5S | [MDL Number]
MFCD21609250 | [MOL File]
1187431-43-1.mol | [Molecular Weight]
693.528 |
| Chemical Properties | Back Directory | [storage temp. ]
Store at -20°C | [solubility ]
insoluble in EtOH; insoluble in H2O; ≥11.2 mg/mL in DMSO with gentle warming and ultrasonic | [form ]
solid |
| Hazard Information | Back Directory | [Description]
In May 2013, the US FDA approved trametinib (also referred to as GSK1120212 and JTP-74057), for the treatment of patients with unresectable or metastatic melanoma with BRAFV600e or BRAFV600K mutations as detected by an FDA-approved test. Extensive lead optimization led to the identification of trametinib which is a potent ATP noncompetitive inhibitor of MEK1 and MEK2 (IC50 =0.7 and 0.9 nM, respectively, with initially unphosphorylated MEK). It also showed inhibitory activity in ACHN and HT-29 cancer cell lines (IC50s of 9.8 and 0.57 nM, respectively). Consistent with its in vitro activity, trametinib showed significant antitumor activity in a KRASG12S A549 tumor xenograft model where near to complete tumor growth inhibition (TGI) was observed at 5.0 and 2.5 mg/kg (92% and 87% TGI, respectively). Broad antitumor activity was seen in other xenograft models as well. A synthetic route to trametinib that employs a base catalyzed rearrangement of a pyrido[2,3-d]pyrimidine core to pyrido[4,3-d]pyrimidine, as a key step has been reported. | [Originator]
Japan Tobacco (Japan) | [Uses]
Trametinib (DMSO Solvate) is a highly potent and selective MEK inhibitor with significant antitumor activity. | [Definition]
ChEBI: An addition compound obtained by combining equimolar amounts of trametinib and dimethyl sulfoxide. Used for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, and who have not received prior BRAF inhibito
treatment. | [Brand name]
Mekinist | [Synthesis]
Commercial 2-fluoro-4-iodoaniline (180) was sequentially subjected
to CDI and cyclopropylamine to generate urea 181 in 96%
yield. This was followed by coupling with cyanoacetic acid in the
presence of mesyl chloride and DMF to furnish imide 182 in 96%
yield. Under basic conditions, imide 182 underwent an
intramolecular cyclization reaction to produce pyrimidine-2,4-
dione 183 in 88% yield. Next, condensation with DMF¨CDMA generated
formamidine 184 in 92% yield, and this was followed by
NaBH4-mediated reduction and subsequent annulation with 2-
methyl-malonic acid (186) to arrive at trione 187 in 58% from
184. Trione 187 was then treated with p-toluenesulfonyl chloride
in Et3N, and the resulting tosylate was exposed to 30-aminoacetanilide
(189) in the presence of 2,6-lutidine and DMA, inducing
an addition-elimination reaction to give pyrido[2,3-d]pyrimidine
190 in 93% yield. The rearrangement of pyrido[2,3-d]pyrimidine
190 with sodium methoxide in THF/MeOH gave pyrido[4,3-
d]pyrimidine (trametinib) in 89% yield. This was then complexed
with a single equivalent of DMSO to produce trametinib DMSO
(XXIV) in 92% yield.
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