857890-39-2

E7080 (Lenvatinib) is a multi-target inhibitor of VEGFR2 and VEGFR3 with IC50 of 4 nM and 5.2 nM, respectively.

ChEBI: A methanesulfonate salt obtained by reaction of lenvatinib with one molar equivalent of methanesulfonic acid. A multi-kinase inhibitor and orphan drug used (as its mesylate salt) for the treatment of various types of thyroid cancer that do not respond to r dioiodine.

Developed by Eisai Inc., lenvatinib mesylate is a vascular endothelial growth factor receptor (VEGF) inhibitor which has activity against VEGF subtypes 1, 2, and 3 and was approved by the FDA in 2015 for the treatment of differentiated thyroid cancer that is either locally recurrent, metastatic, or progressive and did not respond to radioactive iodine treatment. In May 2016, the FDA approved the drug as a combination therapy with everolimus for the treatment of advanced renal cell carcinoma. Because VEGF (and fibroblast growth factor receptors, known as FGFRs) are thought to play a role in cardiovascular signaling pathways, VEGF2R and FGFR inhibition are thought to be the mechanisms behind the primary side effect of lenvatinib mesylate, which is hypertension.

Lenvatinib mesylate works by blocking proteins that signal cancer cells to multiply. It also blocks proteins that signal the formation of new blood vessels that are needed to support tumor growth. Blocking these signals keeps cancer cells from growing.

Lenvatinib is rapidly absorbed after oral administration, with tmax typically observed at 1 to 4 hours postdose. Food does not affect the extent of absorption but slows the rate of absorption. When administered with food to healthy subjects, peak plasma concentrations are delayed by 2 hours.
In vitro binding of lenvatinib to human plasma proteins was high and ranged from 98% to 99% (0.3 – 30 μg/mL, lenvatinib Mesylate). This binding was mainly to albumin with minor binding to α1-acid glycoprotein and γ-globulin. In vitro, the lenvatinib blood-to-plasma concentration ratio ranged from 0.589 to 0.608 (0.1 - 10 μg/mL, lenvatinib Mesylate). Lenvatinib is a substrate for P-gp and BCRP. Lenvatinib is not a substrate for OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, or the BSEP.

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The most prevalent AEs were hypertension (77.8%), fatigue (55.6%), weight loss (51.9%).In addition, there may be fatigue or tiredness, rashes, redness, itching or peeling of the palms and soles of the feet, diarrhoea, nausea, constipation and heartburn.

Starting from commercial aniline 193, a substitution reaction under neutral conditions in warm isopropyl alcohol with a commercial vinyl methoxy derivative of Meldrum’s acid (194) produced enamine 195 in good yield. Next, subjection of 195 to DOWTHERM A at 190 °C affected an intramolecular cyclizative substitution reaction, followed by loss of acetone, and a decarboxylation reaction to furnish quinolone 196. This cyclization reaction, which is a variant of the Conrad-Limpach reaction, is particularly noteworthy given the temperature and pH at which it takes place. Conrad- Limpach cyclizations typically proceed under basic conditions at temperatures well above 240 °C. However, a process was developed by Zeneca in 2004 which involved subjecting 195 to the DOWTHERM heat transfer fluid (commercially available from Dow and Sigma-Aldrich, consisting of a eutectic mixture of biphenyl and diphenyl oxide) allowed the team to lower the temperature required for the reaction, clearly observe bubbling of gas indicating the progress of the reaction, and simple cooling and treatment with ether to facilitated precipitate formation. The resulting solid could be collected by filtration and required no additional purification on scale in 80% yield. Quinoline 196 was then converted to the corresponding chloride using thionyl chloride in refluxing DMF, and the resulting ester 197 was converted to the corresponding amide through the use of 28% aqueous ammonia in warm ethanol, which ultimately produced the key chloroquinoline lenvatinib subunit 198 in 80% yield from 197.
       
Commercial aminophenol 199 was converted to the corresponding carbamate through the use of phenyl chloroformate in essentially quantitative yield prior to subjection to cyclopropylamine in chilled DMF, which ultimately furnished urea 201 in 77% overall yield from 200. Next, exposure of phenol 201 to chloroquinoline 198 in the presence of potassium t-butoxide followed by treatment with methanesulfonic acid and acetic acid resulted in clean formation of lenvatinib mesylate (XXV) in 96% yield across the two-step sequence.

Lenvatinib is metabolised by CYP3A and aldehyde oxidase. Following administration of radiolabelled lenvatinib to 6 patients with solid tumours, approximately two-thirds and one-fourth of the radiolabel were eliminated in the faeces and urine, respectively

lenvatinib Mesylate is a white powder sparingly soluble in acetic acid and slightly soluble in water. It is very slightly soluble in 1,3-dimethyl-2-imidazolidinone and practically insoluble in acetonitrile, dehydrated ethanol, 1-propanol, 2-propanol, 1-octanol, and isopropyl acetate. In aqueous solutions, lenvatinib mesylate is slightly soluble in 0.1 mol/L HCl and practically insoluble in Britton-Robinson buffer, pH 3-11.