1100598-32-0 Usage
Description
Tepotinib is a highly selective inhibitor against MET. In xenograft models, acquired resistance to EGFR TKIs via secondary EGFR T790 M mutations can be overcome with tepotinib treatment.
Uses
EMD 1214063 is a novel ATP-comptetitive inhibitor of the MET hepatocyte growth factor receptor and a novel kinase inhibitor and a therapeutic agent for neuroblastoma. Potent c-MET inhibitor.
Mechanism of action
Tepotinib is a Kinase Inhibitor. The mechanism of action of tepotinib is as a Mesenchymal Epithelial Transition Inhibitor, and P-Glycoprotein Inhibitor.
Pharmacology
Tepotinib is a highly-selective inhibitor of MET kinase activity, with an average IC50
of approximately 1.7 nmol/L. It has a moderate duration of action
necessitating once-daily administration. ?Tepotinib has been associated
with the development of interstitial lung disease (ILD)/pneumonitis,
which can sometimes be fatal. Patients should be monitored closely for
signs of new or worsening respiratory symptoms (e.g. dyspnea, cough),
and treatment with tepotinib should be immediately withheld if
ILD/pneumonitis is suspected. If no other potential causes of
ILD/pneumonitis are identified, therapy with tepotinib should be
suspended indefinitely.
Clinical Use
Tepotinib is currently being evaluated in combination with EGFR TKI gefitinib and also a separate trial in NSCLC patients with MET exon 14 skipping mutation and MET amplification.
Side effects
anxietychest pain or tightnessdifficult or labored breathingdizziness or lightheadednessfast heartbeatfever or chillsgeneral feeling of discomfort or illnessmuscle or bone pain
Synthesis
The synthesis of Tepotinib is as follows:Acetonitrile (700 ml) was added to the reaction vessel, and the compound represented by formula 7a (37.63 g, 0.1 mol), the compound represented by formula 8 (23.66 g, 0.12 mol), and potassium carbonate (34.55 g, 0.25 mol) were added under stirring.and tetrabutylammonium bromide (1.93g, 0.006mol), the reaction system was stirred and heated to reflux, and the reaction was stirred at reflux for 12h. After the reaction was completed, the temperature was cooled to room temperature, the reaction solution was concentrated under reduced pressure to dryness, and ethanol (360ml) was added. ), stir to dissolve, slowly add 1.5 mol/l hydrochloric acid aqueous solution dropwise, adjust the pH value to 1-2, cool down to 5-7 °C, stir and crystallize for 6 h, filter, and vacuum dry the solid at 45 °C for 6 h to obtain formula 1. The compound (44.42 g) was shown in a yield of 81.2% and a purity of 99.7% by HPLC.
Drug interactions
Tepotinib is indicated for the treatment of adult patients with
metastatic non-small cell lung cancer (NSCLC) who have
mesenchymal-epithelial transition (_MET_) exon 14 skipping alterations.
Metabolism
Tepotinib is metabolized primarily by CYP3A4 and CYP2C8, with some
apparent contribution by unspecified UGT enzymes. The metabolite M506 is
the major circulating metabolite, comprising approximately 40.4% of
observed drug material in plasma, while the M668 glucuronide metabolite
has been observed in plasma at much lower quantities (~4% of an orally
administered dose). A total of 10 phase I and phase II metabolites have
been detected following tepotinib administration, most of which are
excreted in the feces.
Check Digit Verification of cas no
The CAS Registry Mumber 1100598-32-0 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,1,0,0,5,9 and 8 respectively; the second part has 2 digits, 3 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 1100598-32:
(9*1)+(8*1)+(7*0)+(6*0)+(5*5)+(4*9)+(3*8)+(2*3)+(1*2)=110
110 % 10 = 0
So 1100598-32-0 is a valid CAS Registry Number.
1100598-32-0Relevant articles and documents
NOVEL POLYMORPHIC FORMS OF 3-(1-{3-[5-(1-METHYL-PIPERIDIN-4YLMETHOXY)-PYRIMIDIN-2-YL]-BENZYL}-6-OXO-1,6-DIHYDRO-PYRIDAZIN-3-YL)-BENZONITRILE HYDROCHLORIDE SALT AND PROCESSES OF MANUFACTURING THEREOF
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Page/Page column 16, (2010/08/04)
The present invention relates to hydrochloride solvates of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile and crystalline modifications thereof. The present invention further relates to processes of manufacturing these crystalline modifications as well as their use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, which are caused, mediated and/or propagated by the inhibition, regulation and/or modulation of signal transduction of kinases, in particular by the inhibition of tyrosine kinases, e.g. pathophysiological conditions such as cancer.