Vandetanib solid is found to be stable to both thermal and hydrolytic degradation but a small degree of degradation is observed under stressed photolytic conditions. In solution, vandetanib is degraded under acidic, oxidative and light stress conditions but it is stable under basic conditions.
分解：
Thermal decomposition may produce toxic gases such as carbon monoxide, carbon dioxide, and nitrogen oxides.
Unchanged vandentanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. N-desmethyl-vandetanib is primarily produced by CYP3A4, and vandetanib-N-oxide is primarily produced by flavin–containing monooxygenase enzymes FMO1 and FMO3.
The metabolism of vandetanib seemed to be similar in the toxicology species, rat and dog, as well as in mouse and human. The 2 major metabolites identified in excreta, were N-desmethyl-vandetanib and vandetanib-N-oxide. In mouse, a minor metabolite was also identified as O-desalkyl-vandetanib glucuronid. A glucuronide conjugate was also detected in human urine. Metabolism as well as biliary excretion appears to be most important for the elimination of vandetanib in preclinical species. CYP identification studies in vitro, suggest that CYP3A4 is involved in the formation of N-desmethyl-Vandetanib. vandetanib-N-oxide is formed via FMO1 and FMO3 (FMO=flavine mono-oxygenase). Both these enzymes are also found in kidney indicating that renal excretion might be contributed to the clearance of vandetanib.
Following oral dosing of (14)C-vandetanib, unchanged vandetanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. A glucuronide conjugate was seen as a minor metabolite in excreta only. N-desmethyl-vandetanib is primarily produced by CYP3A4 and vandetanib-N-oxide by flavin-containing monooxygenase enzymes FMO1 and FMO3. N-desmethyl-vandetanib and vandetanib-N-oxide circulate at concentrations of approximately 7-17% and 1.4-2.2%, respectively, of those of vandetanib.
... In plasma, concentrations of total radioactivity were higher than vandetanib concentrations at all time points, indicating the presence of circulating metabolites. Unchanged vandetanib and 2 anticipated metabolites (N-desmethylvandetanib and vandetanib N-oxide) were detected in plasma, urine, and feces. A further trace minor metabolite (glucuronide conjugate) was found in urine and feces. ... Unchanged vandetanib and N-desmethyl and N-oxide metabolites were detected in plasma, urine, and feces.
IDENTIFICATION AND USE: Vandetanib is a white to off white powder that is formulated into film-coated tablets. Vandetanib is a multitargeted tyrosine kinase inhibitor used for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Because of the risk of QT prolongation, torsades de pointes, and sudden death, the US Food and Drug Administration (FDA) requires a Risk Evaluation and Mitigation Strategy (REMS) for vandetanib. Under the terms of the REMS program, vandetanib is available only under a restricted distribution program. It was granted orphan drug status by the FDA. HUMAN EXPOSURE AND TOXICITY: Vandetanib prolongs the QT interval in a concentration-dependent manner. Torsades de pointes (a distinctive polymorphic ventricular tachycardia in which the QRS amplitude varies and the QRS complexes appear to twist around), ventricular tachycardia, and sudden death have all been reported in patients receiving vandetanib. Vandetanib should not be used in patients who have a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure, or in patients with electrolyte disturbances. Hypocalcemia, hypokalemia, and/or hypomagnesemia must be corrected prior to the administration of vandetanib. Other toxicities that are associated with the use of vandetanib and have resulted in fatalities include: severe skin reactions (including Stevens-Johnson syndrome), interstitial lung disease or pneumonitis, ischemic cerebrovascular events, serious hemorrhagic events and heart failure. Vandetanib may also cause fetal harm if administered to pregnant women. Pregnancy should therefore be avoided during vandetanib therapy. Vandetanib was not clastogenic to cultured human lymphocytes. ANIMAL STUDIES: In the rat, a single oral dose at 2000 mg/kg was not tolerated and all animals died or were killed for humane reasons by Day 4. Histopathological findings in these rats included hepatocyte vacuolation, fat deposition and necrosis in the liver, ulceration in the stomach, mucosal single cell necrosis and erosion in the duodenum, and macrophage vacuolation in the spleen. There were no adverse effects in rats dosed at 1000 mg/kg. A single oral dose of vandetanib at 2000 mg/kg to mice was not tolerated and all animals died or were killed for humane reasons on Day 1. A single oral dose of 1000 mg/kg resulted in the death of 1 out of 10 mice. There were no salient histopathology findings except for ulceration in the stomach in 1 animal dosed at 2000 mg/kg. In 1, 6 and 9 month studies, the dose limiting toxicities included gastrointestinal effects in dogs (including loose/abnormal feces, emesis and body weight loss), and skin toxicity and hepatotoxicity in rats. Vandetanib had no effect on copulation or fertility in male rats, while in female rats there was a trend towards increased estrus cycle irregularity, a slight reduction in pregnancy and an increase in post-implantation loss. In rats, vandetanib demonstrated the potential to cause embryo-fetal loss, delayed fetal development, heart vessel abnormalities and precocious ossification of some skull bones. In a rat pre- and post-natal development study, at doses producing maternal toxicity during gestation and/or lactation, vandetanib increased pre-birth loss and reduced post-natal pup growth. Vandetanib showed no mutagenic potential in 4 strains of Salmonella typhimurium (TA1535, TA1537, TA98 and TA100) and 2 strains of Escherichia coli (WP2P and WP2 uvrA) with or without metabolic activation.
In large clinical trials of vandetanib, abnormalities in routine liver tests were common with serum aminotransferase elevations, occurring in up to half of patients and rising above 5 times the upper limit of normal (ULN) 2% to 5% of patients. In prelicensure trials of vandetanib in thyroid cancer, there were no reports of clinically apparent liver injury with jaundice or hepatic failure. Since approval and more wide scale use, there have been no published reports of hepatotoxicity due to vandetanib and the product label does not include discussion of hepatotoxicity. However, many of the kinase inhibitors used in cancer chemotherapy have been implicated in cases of clinically apparent liver injury which typically arises within the first 2 to 12 weeks of therapy, presenting with symptoms of fatigue, nausea and jaundice and a hepatocellular pattern of serum enzyme elevations without immunoallergic or autoimmune features. Several tyrosine kinase inhibitors (imatinib, nilotinib) have also been implicated in causing reactivation of hepatitis B.
◉ Summary of Use during Lactation:No information is available on the clinical use of vandetanib during breastfeeding. Because vandetanib is 90% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is 19 days and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during vandetanib therapy and for 4 months after the last dose.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
Concomitant use of vandetanib with drugs known to prolong the QT interval, including class Ia (e.g., disopyramide, procainamide, quinidine) and class III (e.g., amiodarone, sotalol, dofetilide) antiarrhythmic agents, some anti-infectives (e.g., clarithromycin, gatifloxacin, moxifloxacin), some antipsychotic agents (e.g., chlorpromazine, thioridazine, haloperidol, asenapine, olanzapine, paliperidone, pimozide, quetiapine, ziprasidone), some type 3 serotonin (5-HT3) receptor antagonists used as antiemetic agents (e.g., dolasetron, granisetron, ondansetron), chloroquine, methadone, and tetrabenazine should be avoided. If a drug known to prolong the QT interval must be administered, more frequent ECG monitoring is recommended. If a 5-HT3 receptor antagonist is clinically necessary, some clinicians prefer granisetron because its effects on ECG intervals are less pronounced than those observed with dolasetron or ondansetron.
Inducers of CYP3A4 can alter plasma vandetanib concentrations. Concomitant use of vandetanib with potent CYP3A4 inducers (e.g., carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) should be avoided. St. John's wort (Hypericum perforatum) may unpredictably decrease vandetanib exposure, and concomitant use of vandetanib with this agent also should be avoided.
Slow- peak plasma concentrations reached at a median 6 hours. On multiple dosing, Vandetanib accumulates about 8 fold with steady state reached after around 3 months.
来源:DrugBank
吸收、分配和排泄
消除途径
大约69%的药物在单次给药21天后通过粪便和尿液排出，其中44%在粪便中找到，25%在尿液中。
About 69% was recovered following 21 days after a single dose of vandentanib. 44% was found in feces and 25% in urine.
Vandetanib binds to human serum albumin and a1-acid-glycoprotein with in vitro protein binding being approximately 90%. In ex vivo plasma samples from colorectal cancer patients at steady state exposure after 300 mg once daily, the mean percentage protein binding was 94%.
Within a 21-day collection period after a single dose of (14)C-vandetanib, approximately 69% was recovered with 44% in feces and 25% in urine. Excretion of the dose was slow and further excretion beyond 21 days would be expected based on the plasma half-life. Vandetanib was not a substrate of hOCT2 expressed in HEK293 cells. Vandetanib inhibits the uptake of the selective OCT2 marker substrate 14C-creatinine by HEK-OCT2 cells, with a mean IC50 of 2.1 ug/mL. This is higher than vandetanib plasma concentrations (0.81 ug/mL) observed after multiple dosing at 300 mg. Inhibition of renal excretion of creatinine by vandetanib provides an explanation for increases in plasma creatinine seen in human subjects receiving vandetanib.
Radiosynthesis of [11C]Vandetanib and [11C]chloro-Vandetanib as new potential PET agents for imaging of VEGFR in cancer
摘要：
Vandetanib (ZD6474) and its chlorine analogue chloro-Vandetanib are potent and selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors with low nanomolar IC50 values. [C-11]Vandetanib and [C-11]chloro-Vandetanib, new potential PET agents for imaging of VEGFR in cancer, were first designed, synthesized and labeled at nitrogen and oxygen positions from their corresponding N- and O-des-methylated precursors, in 40-50% decay corrected radiochemical yield and 370-555 GBq/mu mol specific activity at end of bombardment (EOB). (C) 2011 Elsevier Ltd. All rights reserved.
[EN] 2-QUINOLONE DERIVED INHIBITORS OF BCL6<br/>[FR] INHIBITEURS DE BCL6 DÉRIVÉS DE 2-QUINOLONE
申请人：CANCER RESEARCH TECH LTD
公开号：WO2018215798A1
公开（公告）日：2018-11-29
The present invention relates to compounds of formula I that function as inhibitors of BCL6(B- cell lymphoma 6) activity: Formula I wherein X1, X2, X3, R1, R2, R3, R4 and R5 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer,as well as other diseases or conditions in which BCL6 activity is implicated.
SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
申请人：BLUM Andreas
公开号：US20140135309A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I
wherein Ar, R
1
and R
2
are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
[EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2014072244A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
[EN] METALLOENZYME INHIBITOR COMPOUNDS<br/>[FR] COMPOSÉS INHIBITEURS DE MÉTALLOENZYMES
申请人：VPS 3 INC
公开号：WO2018165520A1
公开（公告）日：2018-09-13
Provided are compounds having HDAC6 modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by HDAC6.
提供具有HDAC6调节活性的化合物，以及通过HDAC6介导的治疗疾病、疾病或症状的方法。
CHROMENONE DERIVATIVES
申请人：BARLAAM Bernard Christophe
公开号：US20110098271A1
公开（公告）日：2011-04-28
The invention concerns chromenone derivatives of Formula I
or a pharmaceutically-acceptable salts thereof, wherein each of R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, n and R
9
has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders.
