VEGFR-2 inhibitor - Knowledge (XXG)

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When substituents are added on pazopanib with different electronic effects at the benzene ring the inhibition to the kinase changes. Regarding the steric effect on position R1 and R2, a hydrogen in position R1 and a trifluoro-ether in R2 have the most inhibitory effect on VEGFR-2, which can be the effect of the electronegative groups. There is a steric hindrance of the indazole heterocycle, which can play an important role in the interaction with the tyrosine kinase receptor inhibition.

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CYP3A4 inducers will do the opposite. Grapefruit juice is a CYP3A4 inhibitor and should be avoided when taking pazopanib. It is also a weak inhibitor of other liver enzymes, CYP2C8 and CYP2D6. Axitinib is metabolized by CYP3A4 and UGT1A1. Strong inhibitors of CYP3A4 will increase the plasma concentration of axitinib, while weak inhibitors have less effect on the plasma concentration. Strong inducers of CYP3A4 will decrease the plasma concentration of axitinib and should be avoided.

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La, Daniel S.; Long, Alexander; Martin, Matthew W.; Neervannan, Sesha; Patel, Vinod F.; Potashman, Michele; Regal, Kelly; Roveto, Phillip M.; Schrag, Michael L.; Starnes, Charlie; Tasker, Andrew; Teffera, Yohannes; Wang, Ling; White, Ryan D.; Whittington, Douglas A.; Zanon, Roger (March 2008). "Naphthamides as Novel and Potent Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors: Design, Synthesis, and Evaluation".

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in several pathways in tumor development. Intedanib is a multiple tyrosine kinase inhibitor and is the first drug to treat idiopathic pulmonary fibrosis. Indol derivatives with 1-NH of 2-indolinone motif that is an H-bond donor, and 2-carbonyl oxygen that acts as an H-bond acceptor, bind with Glu915 and Cys917, respectively. These compounds have basic amine side chains or nitrogen heterocycles and provide ideal solubility and

769:. Increased stability against degradation by liver enzymes can be acquired by adding a deuterium to heterocyclic compounds. Novel urea compounds with pentafluoro-sulfane substitute on a phenyl group show better protein kinase inhibition in diseases like cancer when compared to aryl-urea compounds with either quinazoline or pyrimidine moieties. N-substituted phenyl N’-substituted heterocyclic urea compounds give an 586:). Sunitinib is metabolized in the liver by CYP3A4. It interacts with inducers and inhibitors of CYP3A4 leading to a decrease or increase in the plasma concentration of particular drugs metabolized by the same pathway. It will not change the amount of drug metabolized by the enzyme, because it does not inhibit or induce the enzyme directly. Sunitinib is a substrate of 757: 621:, so it is cautionary to administer sorafenib with these drugs as it may alter the plasma concentration. Sorafenib is metabolized by CYP3A4 and UGT1A9. This means that drugs metabolized by these pathways have to be carefully administered. Sorafenib's inhibition of UGT1A9 and UGT1A1 may increase plasma concentration of other drugs. The same goes for the 802:

side chain has very good VEGFR-2 potency, with an IC50 of 65 nM. N-indol-1-amide compound is a possible anti-tumor drug in combination with other anticancer treatment and has an IC50 value of 31 nM. There are many indol derivatives with different side chains that target multiple kinases and take part

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Two indol derivatives that target the VEGF pathway, semaxanib and sunitinib, have been developed. The former is potent but was inefficient in clinical trials and the latter has many side effects. There is need for a drug with pharmacological effects similar to semaxanib and sunitinib, but it needs to

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Jost, Lorenz M.; Gschwind, Hans-Peter; Jalava, Tarja; Wang, Yongyu; Guenther, Clemens; Souppart, Claire; Rottmann, Antje; Denner, Karsten; Waldmeier, Felix; Gross, Gerhard; Masson, Eric; Laurent, Dirk (1 November 2006). "Metabolism and Disposition of Vatalanib (PTK787/ZK-222584) in Cancer Patients".

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Harmange, Jean-Christophe; Weiss, Matthew M.; Germain, Julie; Polverino, Anthony J.; Borg, George; Bready, James; Chen, Danlin; Choquette, Deborah; Coxon, Angela; DeMelfi, Tom; DiPietro, Lucian; Doerr, Nicholas; Estrada, Juan; Flynn, Julie; Graceffa, Russell F.; Harriman, Shawn P.; Kaufman, Stephen;

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If the indazole ring is kept the same, replacing 5-amino-2-methylbenzenesulfonamide with another arylamine at position 2 of the pyrimidine, gives inhibitory effect on VEGFR-2 and c-Kit. For R2, two groups can show this effect on the compound, an ether group on one, and on the other a chloride group.

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growth factor related genes. Simultaneous inhibition of VEGF and FGF receptors in FGFR1 dependent tumors could be therapeutically advantageous. Lucitanib has been shown to have promising efficacy, a manageable side-effect profile and clinical benefits in both FGF-aberrant and angiogenesis-sensitive

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has approved three drugs, bevacizumab, sunitinib and sorafenib, that were developed for antiangiogenic actions and are used in the treatment of patients with specific cancer types. All of these drugs have the mechanism of inhibiting VEGF signalling by blocking either the function of the VEGF ligand

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sites of the human VEGFR-2 followed by VEGF binding. Autophosphorylated VEGFR-2 is required for activation of several downstream pathways, which are hyperactivated in some tumors. These signaling pathways are important in tumor angiogenesis, which stimulates tumor growth by supplying the tumor with

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of 2230 L, which indicates distribution into tissues. Sunitinib is metabolised mostly by CYP3A4 and has a half life of 40–60 hours. Nintedanib reaches maximum plasma concentration 2–4 hours post-dose. The drug is 97,8% protein bound and is preferentially distributed in plasma. Only a minor part of

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drug itraconazole may be and inhibitor for VEGFR-2 and could be used in treatments that VEGFR-2 plays a role. 3-phenyl-5-ureidoisothiazole-4-carboximide and 3-amino-5-phenylisothiazole derivatives inhibit, modulate and regulate tyrosine kinase signal and can be used for treatment of disorders that

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Regorafenib and sorafenib reach mean peak plasma level in about 3 or 4 hours after a single oral dose. A high-fat meal decreases their absorption, while a low-fat meal may increase it, in comparison to taking the drugs in a fasting condition. In vitro protein binding is 99,5% for both drugs. The

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Lenvatinib, Vandetanib and Cabozantinib are drugs that belong to this group. Novel biphenyl tricyclic quinazoline compounds and aryloxy quinolone derivatives are multiple kinase inhibitors. They are less likely to lead to drug resistance than selective inhibitors, which increases life expectancy.

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attached to it via a spacer moiety. MPEG3-9-semaxanib derivatives are 10 times more active against VEGFR-2 than sunitinib. Compounds with sunitinib heterocyclic moiety but different amide side chains inhibit VEGFR-1 and VEGFR-2 and regulate disorders. Another compound with sunitinib heterocyclic

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and CYP3A4. It inhibits P-glycoprotein, therefore it can increase the plasma concentration of drugs which are P-glycoprotein substrates. Pazopanib is metabolized in the liver by CYP3A4 enzyme. Strong CYP3A4 inhibitors, other than pazopanib, can increase the plasma concentration of pazopanib, and

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Axitinib has short half-life, ranging from 2.5 to 6.1 hours, and therefore steady state should be reached in 2–3 days after the first dose. Peak plasma concentration is reached in 2.5 to 4.1 hours. In vitro protein binding is over 99%. Axitinib is primarily metabolized in the liver by CYP3A4/5.

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atom in the benzazepine inhibit multiple targets and have better in vitro enzyme inhibiting activity. 3-chloro derivatives and 3-methoxy-N-methyl-2-pyridine carboxamide derivatives inhibit, modulate and regulate tyrosine kinase signal transduction. VEGFR2 related diseases are treated with the

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atom in the heterocyclic ring is hypothesized to enhance potency on VEGFR-2 inhibition. Compounds with thieno pyridine urea moiety are inhibitory for VEGF receptor signaling and HGF receptor signaling. HGF and HGF receptors undermine the activity of VEGF inhibition. Pyridine derivatives with

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Inhibition of angiogenesis including VEGFR-2 inhibitors has been of much interest and research in recent decades because angiogenesis is required for tumors to grow beyond a diameter of 1–2 mm. Many small molecular drugs and biological macromolecules targeting VEGFRs or blocking signal

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Pazopanib reaches maximum plasma concentration 3.5 hours post-dose. Pazopanib is about 99% protein bound to human plasma protein. Metabolism of pazopanib is mediated primarily by CYP3A4 and the half-life of the drug is about 30.9 hours. Elimination of pazopanib is primarily with faeces.

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Bevacizumab is a function-blocking monoclonal antibody that binds selectively to VEGF. Generally it is well tolerated and safe but can have adverse effects which can be intensified by chemotherapeutic agents used at the same time. For bevacizumab the most common adverse effects are

578:. Lenvatinib induces CYP3A but not UGT1A1 and UGT1A4. Use of other drugs, especially ones metabolized by the liver enzyme CYP3A, should be monitored in case their plasma concentration changes. In vitro studies have shown that lenvatinib inhibits organic anion transporters 1 and 3 ( 1578:

Bilbao-Meseguer, Idoia; Jose, Begoña San; Lopez-Gimenez, Leocadio R; Gil, Maria A; Serrano, Laura; Castaño, Mikel; Sautua, Saioa; Basagoiti, Amaya De; Belaustegui, Ainhoa; Baza, Beatriz; Baskaran, Zuriñe; Bustinza, Alazne (8 January 2014). "Drug interactions with sunitinib".

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Oxetane 3,3-dicarboxamide compounds are possible inhibitors of tumor angiogenesis and metastasis, and may also be effective against viral infections. A 1,6-naphyridine-4-ketone fused heterocyclic derivative inhibits various kinases and the activity of tumor cells. The

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is an antiangiogenic VEGFR inhibiting molecule which is being researched as a potential treatment of solid tumors. Vatalanib inhibits VEGFR 1-4 although it has greater potency as an inhibitor of VEGFR 1-2. At concentrations under 10 μM, Vatalanib does not have

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Soria, J.- C.; DeBraud, F.; Bahleda, R.; Adamo, B.; Andre, F.; Dientsmann, R.; Delmonte, A.; Cereda, R.; Isaacson, J.; Litten, J.; Allen, A.; Dubois, F.; Saba, C.; Robert, R.; D'Incalci, M.; Zucchetti, M.; Camboni, M. G.; Tabernero, J. (5 September 2014).

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are caused by unregulated tyrosine kinase signal transduction, including cell growth, metabolic and blood vessel proliferative disorders. Thioether derivatives can be used to treat all forms of cancer and target multi target protein kinase inhibitors.

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Hypertension is one of the most common side effects regarding inhibition of VEGF signalling. VEGF increases synthesis of NO through upregulation of endothelial NO synthase and therefore inhibition of VEGF diminishes NO synthesis. Decrease in NO causes

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compounds mentioned above in conjugation with other cancer therapies. 1-(5-tert-butyl-2-aryl-pyrazol-3-yl)-3- pyrazin-8-yl) oxy] phenyl] urea compounds are RAF inhibitors and treat disorders associated with mutated forms of RAF, like cancer,

325:. Treatment with VEGF inhibitors suppresses cellular signalling pathways that are important in microvasculature regulation and maintenance. The effects on normal organs can then lead to vascular disturbances and regression of blood vessels. 129:

VEGFR-2 are a part of the VEGF family. The other receptors in the family are VEGFR-1 and VEGFR-3. These receptors are a type of transmembrane kinase receptors and have similar structure. They have an extracellular part that is made up of an

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Guffanti, Federica; Chilà, Rosaria; Bello, Ezia; Zucchetti, Massimo; Zangarini, Monique; Ceriani, Laura; Ferrari, Mariella; Lupi, Monica; Jacquet-Bescond, Anne; Burbridge, Mike F.; Pierrat, Marie-Jeanne; Damia, Giovanna (15 December 2016).

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of CYP3A4, and glucuronidized by UGT1A9. Their half life ranges from 20 to 48 hours. Most of the administered dose should be out of the system in around 14 days. The drugs are mostly excreted in faeces, around 70-80%, but also in urine.

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derivatives with a diaryl-amide or diaryl-urea substructure have B-Raf mutant kinase inhibition activity. Some novel quinazoline derivatives inhibit Raf kinase selectively and have less effect on inhibition of VEGFR-2 and EGFR kinase. A

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cascade, which activates several downstream enzymatic pathways. The signaling inhibition of VEGFR is through tumor vessels and not the tumor cells. Reduction of VEGF expression reduces blood flow to tumor and stops tumor angiogenesis.

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or lymphangiogenesis, leading to anticancer activity. Generally they are small, synthesised molecules that bind competitively to the ATP-site of the tyrosine kinase domain. VEGFR-2 selective inhibitor can interrupt multiple

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Binding to VEGF receptor induces dimerization, which modifies the conformation in the intracellular domain. This modification leads to the exposure of the ATP-binding site, which causes ATP binding on the receptor and also

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is a multi VEGFR 1-3 inhibitor being tested as a maintenance treatment for patients with platinum sensitive relapsed ovarian cancer. Cediranib stops blood flow to the site of the tumour and thereby inhibits its growth.

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or antiproliferative effects on cells that do not express VEGF. Specific inhibition of tumor-induced angiogenesis like the inhibition by Vatalanib can both prevent ongoing growth of tumors and the metastatic potential.

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Sunitinib is a small molecule inhibitor which inhibits phosphorylation of VEGF receptor among other receptors. Sunitinib is mostly well tolerated. Common adverse effects which have an incidence rate of 20% are fatigue,

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Kubota, K.; Ichinose, Y.; Scagliotti, G.; Spigel, D.; Kim, J. H.; Shinkai, T.; Takeda, K.; Kim, S.- W.; Hsia, T.- C.; Li, R. K.; Tiangco, B. J.; Yau, S.; Lim, W.- T.; Yao, B.; Hei, Y.- J.; Park, K. (13 January 2014).

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and pancreatic isle have also been known to regress as an effect of VEGF inhibition. The thyroid-hypothalamic feedback loop can also be impaired due to VEGF inhibition, followed by raised TSH blood concentration.

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can occur when VEGF is inhibited as VEGF promotes endothelial cell survival and helps maintaining vascular integrity. When VEGF is inhibited, the regenerative capacity of endothelial cells may diminish and

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Urea derivatives on the market are Regorafenib and Sorafenib. The urea derivatives block the VEGFR and/or one or more protein kinases and can therefore modulate, regulate and/or inhibit tyrosine kinase

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between 15 nM and 1 μM for VEGFR-2. Having a 1H-indole-1-carboxamide scaffold on aryl-urea compounds results in added VEGFR-2 potency and selectivity and gives an IC50 of 3nM against the receptor.

1028:. In 2004 the monoclonal antibody bevacizumab became the first VEGFR inhibitor to be approved for cancer therapy. The first small molecular VEGFR-2 inhibitor to be approved was sunitinib in 2006. 989:

the biotransformation of nintedanib is caused by CYP3A4 as the prevalent metabolic reaction for nintedanib is a hydrolytic cleavage of esterases. The half-life of nintedanib is about 10–15 hours.

88:. VEGFR-2 is closely related to VEGFR-1 for they have common and specific ligands but VEGFR-2 is a highly active kinase while VEGFR1 is an impaired receptor tyrosine kinase. This receptor is a 1895: 439:

Sorafenib is a small molecule inhibitor of many tyrosine kinase receptors such as VEGFR-2. Side effects are in most cases mild to moderate such as rash, hand-foot skin reaction, diarrhea and

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cell development and VEGFR-3 (FLT-4) for lymphatic endothelial cell development. Binding of VEGF to the VEGFR induces a conformational change in the receptor producing a signaling pathway.

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and bleeding. Uncommon side effects are cardiac ischaemia or infarction, gastrointestinal perforation, life-threatening haemorrhage and reversible posterior leukoencephalopathy syndrome.

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Qi, Haofei; Ligong, Chen; Liu, Bingni; Wang, Xinran; Long, Li; Liu, Dengke (15 February 2014). "Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents".

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bonds with the hydrophobic pocket of VEGFR-2, especially the terminal phenyl group substituted by chloride in the para-position. Quinolone-urea containing VEGFR inhibitors will bind to

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Plasma concentration of sorafenib and paclitaxel may be increased when the drugs are co-administered along with carboplatin. This has no effect on carboplatin. It also increases the

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ranging from 1–4 hours for Lenvatinib to 4–10 hours for cabozatinib. Food can slow down the absorption rate but should not affect the extent of the absorption. All drugs have high

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30-60% of the drug is excreted in faeces, and about 23% in urine. Regorafenib is a pyridine derivative, but also a urea derivative and has therefore been covered in that section.

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Conjugated 3-(indolyl)- and 3-(azaindolyl)-4-arylmaleimide compounds can induce apoptosis in cancer cells and therefore may have use in cancer therapy, including colorectal and

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is a tyrosine kinase activity inhibitor, highly selective for VEGFR types 1-3, FGFR types 1-2 and PDGFR alpha/beta. Tumor types such as breast carcinoma show amplification of

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Peng, Fan-Wei; Liu, Da-Ke; Zhang, Qing-Wen; Xu, Yun-Gen; Shi, Lei (23 June 2017). "VEGFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012-2016)".

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is a small-molecule multikinase inhibitor highly selective for VEGFR 1-3, PDGFR and KIT. The drug has shown anti-tumor activity as a monotherapy in advanced solid tumors.

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Musumeci, Francesca; Radi, Marco; Brullo, Chiara; Schenone, Silvia (25 October 2012). "Vascular Endothelial Growth Factor (VEGF) Receptors: Drugs and new inhibitors".

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family contains three members, which are all receptor tyrosine kinases (VEGFR-1, VEGFR-2 and VEGFR-3). VEGFR-1, or FLT-1 (fms-like tyrosine kinase), are important for

1791:"Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC): Asian subgroup analysis" 594:. It acts as an inhibitor for both transporters, especially for ABCG2. Therefore, drugs that are substrates of these carriers will have modified pharmacokinetics. 633:

or inducers of CYP3A4 can decrease plasma concentration of sorafenib. CYP3A4 inhibitors are unlikely to affect sorafenib. Sorafenib is a competitive inhibitor of

535:. Inhibition of VEGF is implicated as a factor in the pathophysiology of the disease but has not yet been replicated after VEGF inhibition in preclinical models. 1142:

Li, Chunpu; Ai, Jing; Zhang, Dengyou; Peng, Xia; Chen, Xi; Gao, Zhiwei; Su, Yi; Zhu, Wei; Ji, Yinchun; Chen, Xiaoyan; Geng, Meiyu; Liu, Hong (3 April 2015).

807:. These compounds are promising anti-cancer and anti-fibrosis agents, inhibiting various protein tyrosine kinases. They have higher efficiency, lower 523:

Reversible posterior leukoencephalopathy is often attributed to hypertensive encephalopathy as well as endothelial dysfunction. This can cause focal

598: 210:, which binds selectively to VEGF. It is used as an injection therapy, often in combination with other drugs. It is used in combination with 5- 1552: 877: 142:

part of the receptor consists of a juxtamembrane (the tyrosine kinase domain), which is divided to proximal and distal kinase domains and a

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Pyridine derivatives with thiazolyamino-substituted heterocycle derivatives are kinase inhibitors. They show antiangiogenesis activity and

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capillary endothelial cells and is activated by VEGF. Proteinuria is in most cases asymptomatic and usually decreases when treatment ends.

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is used for the treatment of advanced gastric cancer. It is often diagnosed in late stages because there are no early signs or symptoms.

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Pazopanib is a multi-targeted tyrosine kinase receptor inhibitor. The structure is formed by indazole, pyrimidine and a benzene ring.

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4-quinazolinamine heterocyclic compounds and 2-chloro-4-anilino-quinazoline derivatives inhibit tumor vessel generation and restrain

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is common when VEGF signalling is inhibited which shows how important VEGF is for normal renal function. VEGFR-2 can be found on the

2076: 892: 2250: 2105: 2047: 2134: 2018: 1007: 2221: 2192: 2163: 1683:"Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors" 1523: 1144:"Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-alpha]pyridine Derivatives as Potent c-Met Inhibitors" 820: 708: 197: 904: 266:

is administered orally for the treatment of colorectal cancer, gastrointestinal stromal cancer and hepatocellular carcinoma.

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benzazepine have stronger selectivity and anti-tumor activity and less toxic side effects. They target many receptors like

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Impaired wound healing can be an adverse effect of VEGF inhibition as angiogenesis is an important step in wound healing.

273: 20: 479: 373: 170:, FLT3 (Fms-like tyrosine kinase-3) and KIT (stem cell factor receptor). Sorafenib is used in the treatment of advanced 954:, ranging from 90-99%. Vandetanib and cabozatinib are metabolized mainly by CYP3A4, while lenvatinib is metabolized by 349: 222:. In advanced non-small cell lung cancer bevacizumab (Avastin) is used as a first-line treatment in combination with 179: 77: 1622: 943: 297: 24: 728:

in position N1 on quinolone and quinazoline derivatives behaves as a hydrogen bond receptor and interacts with

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is used as an oral drug which inhibits angiogenesis and tumor cell growth in VEGFR-2 and VEGFR-3 (inhibits the

81: 1468: 1381: 1352: 532: 849: 57: 1413: 985: 913: 725: 570:, which also happens to be a metabolic enzyme for the drug. It inhibits the UDP-glucuronosyltransferases 520:, the inhibition of VEGF leads to decrease in both chemicals which contributes to thromboembolic events. 1923:"The Tyrosine Kinase Inhibitor Cediranib for Non-small Cell Lung Cancer and Other Thoracic Malignancies" 947: 538: 456: 257: 93: 984:

Sunitinib's peak plasma level is reached 6–12 hours post-dose. The drug is 95% protein bound and has a

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and via other pathways. The drugs are eliminated mostly in faeces, but also in urine. Vandetanib has a

1651: 1442: 972: 293: 171: 1553:"The US FDA grants Apatinib Orphan Drug Designation for Treatment of Gastric Cancer – LSK BioPharma" 766: 463:. Hypertension caused by VEGF inhibition can usually be treated with oral antihypertensive agents. 377: 309: 240:

are used for the treatment of progressive and locally advanced differentiated thyroid cancer (DTC).

207: 105: 1497: 516:, possibly leading to either thrombosis or haemorrhage. Since VEGF increases production of NO and 831: 811:, fewer side effects, favorable preparation technology and favorable physicochemical properties. 591: 429: 389: 37: 33: 843:, VEGFR2, EGFR and therefore show inhibitory activity on a variety of tumors. Compounds with no 443:, and occur in about 33-38% patients using sorafenib. Other side effects are mild hypertension, 188:

is an oral drug that inhibits the phosphorylation of all the VEGF receptors, PDGFR-ß, KIT FLT3,

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be less toxic. MPEG3-9-semaxanib is semaxanib with an additional water-soluble, non-peptidic

741: 372:. Serious adverse effects connected to bevacizumab are infrequent but among those listed are 1984: 1934: 1858: 1812: 1802: 1760: 1744: 1694: 1588: 1321: 1313: 1245: 1163: 1155: 1111: 1055: 861: 804: 745: 729: 513: 452: 308:

through different protein tyrosine phosphatases. This can then lead to the initial receptor

1733:"In Vitro and In Vivo Activity of Lucitanib in FGFR1/2 Amplified or Mutated Cancer Models" 1025: 951: 857: 542: 524: 487: 322: 215: 159: 118: 296:

on specific tyrosine residues. Tyrosine phosphorylation on the receptor is regulated by

276:. Tests for liver function have to be made to modify doses before the therapy can start. 109:

oxygen and nutrients. VEGFR-2 is overexpressed in several cancers, for example ovarian,

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but it is only used on patients who have already received an anti-angiogenic therapy.

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regression around the follicles of the thyroid. The fenestrated capillaries of the

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pathways, they are inhibited by sorafenib. Giving sorafenib in combination with

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can be caused by VEGF inhibition although the mechanism is unknown. Abscesses,

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transduction of VEGF/VEGFR have been approved for clinical use or entered

196:. Sunitinib is used in the treatment of advanced renal cell carcinoma and 865: 844: 808: 794: 618: 409: 405: 357: 279: 247: 114: 97: 92:

in responses in the endothelial cells of VEGF. These regulations include

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Pyridine derivatives on market are axitinib, regorafenib and apatinib.

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development, VEGFR-2 (KDRor FLK-1 (fetal liver kinase)) are vital to

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residue of the receptor via the carbonyl oxygen, and interact with

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are used orally for the treatment of advanced renal cell carcinoma.

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Indolin derivatives on the market are Sunitinib and Intedanib.

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Sunitinib structure. First small molecular VEGFR-2 inhibitor.

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or other symptoms from the gastrointestinal tract as well as

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has been reported as an adverse effect of VEGF inhibition.

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could be exposed on the plasma membrane or the underlying

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Pharmacokinetics of Quinoline and quinazoline-derivatives

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populations leading to a phase II program being planned.

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as a first-line treatment of metastatic carcinoma in the

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of 19 days, while cabozatinib’s half-life is 99 hours.

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VEGF inhibitors in the treatment of cancer often cause

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is one such, since thyroid function can be damaged by

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Nikolinakos, Petros; Heymach, John V (1 June 2008).

398:reversible posterior leukoencephalopathy syndrome 1097: 1095: 1093: 1091: 1089: 1087: 1085: 1675: 1673: 1295: 1293: 1291: 1289: 1287: 895:Mechanism of pazopanib from indolin derivative. 1285: 1283: 1281: 1279: 1277: 1275: 1273: 1271: 1269: 1267: 1231: 1229: 1227: 1225: 1223: 1221: 1219: 1217: 1215: 1213: 1211: 1209: 1207: 1205: 1203: 1201: 1199: 1197: 1195: 1193: 1191: 1189: 1187: 971:drugs are mainly metabolized in the liver by 8: 1977:Bioorganic & Medicinal Chemistry Letters 1970: 1968: 1966: 1408: 1406: 1347: 1345: 1137: 1135: 1133: 166:(platelet-derived growth factor receptor), 1002:Pharmacokinetics of pyrimidine derivatives 1938: 1816: 1806: 1764: 1698: 1325: 1167: 993:Pharmacokinetics of pyridine derivatives 980:Pharmacokinetics of indoline derivatives 1300:Kamba, T; McDonald, D M (22 May 2007). 1037: 908:3-amino-5-phenylisothiazole derivative. 1581:Journal of Oncology Pharmacy Practice 1238:Expert Opinion on Therapeutic Patents 900:Other small molecule VEGFR inhibitors 694:Quinoline and quinazoline-derivatives 689:Structure-activity relationship (SAR) 566:Lenvatinib inhibits the liver enzyme 7: 966:Pharmacokinetics of urea derivatives 384:, complications with wound healing, 946:is variable within the group, with 25:tyrosine kinase receptor inhibitors 732:residue. The terminal substituent 376:, arterial thromboembolic events, 14: 494:have been related to some cases. 834:in tumor cells. The presence of 1851:Drug Metabolism and Disposition 1148:ACS Medicinal Chemistry Letters 198:gastrointestinal stromal tumors 1632:. Food and Drug Administration 1478:. Food and Drug Administration 1449:. Food and Drug Administration 1423:. Food and Drug Administration 1391:. Food and Drug Administration 1362:. Food and Drug Administration 1104:Journal of Medicinal Chemistry 1048:Journal of Medicinal Chemistry 531:, and even a breakdown in the 1: 1559:. LSK BioPharma. 19 June 2017 1250:10.1080/13543776.2017.1344215 274:idiopathic pulmonary fibrosis 272:is used for the treatment of 36:involved in tumor, including 21:kinase insert domain receptor 1940:10.1097/JTO.0b013e318174e910 1927:Journal of Thoracic Oncology 480:Gastrointestinal perforation 374:gastrointestinal perforation 2260:. European medicines agency 2231:. European medicines agency 2202:. European medicines agency 2173:. European medicines agency 2144:. European medicines agency 2115:. European medicines agency 2086:. European medicines agency 2057:. European medicines agency 2028:. European medicines agency 1533:. European medicines agency 748:residue via two NH groups. 350:upper respiratory infection 2354: 2338:Tyrosine kinase inhibitors 2280:"Avastin approval history" 1989:10.1016/j.bmcl.2014.01.003 1737:Neoplasia (New York, N.Y.) 180:non-small cell lung cancer 178:, metastatic melanoma and 78:vascular endothelial cells 2306:"Sutent Approval History" 1749:10.1016/j.neo.2016.11.008 1306:British Journal of Cancer 613:but decreases the AUC of 72:VEGFR-2 is a 210-230 kDa 1593:10.1177/1078155213516158 176:hepatocellular carcinoma 82:hematopoietic stem cells 858:immunological disorders 850:proliferative disorders 58:hematopoietic stem cell 1863:10.1124/dmd.106.009944 1502:reference.medscape.com 1318:10.1038/sj.bjc.6603813 1011: 986:volume of distribution 914:gastric adenocarcinoma 909: 896: 881: 872:Pyrimidine derivatives 824: 786: 761: 703: 685: 1808:10.1093/annonc/mdt552 1700:10.1093/annonc/mdu390 1009: 907: 894: 880:Pyrimidine structure. 879: 822: 784: 759: 702:Quinazoline structure 701: 683: 539:Endocrine dysfunction 457:peripheral resistance 23:(KDR) inhibitor, are 973:oxidative metabolism 815:Pyridine derivatives 294:transphosphorylation 172:renal cell carcinoma 62:vascular endothelial 1900:www.astrazeneca.com 1110:(24): 10797–10822. 823:Pyridine structure. 777:Indolin derivatives 767:signal transduction 684:Quinalone structure 533:blood–brain barrier 436:and mild bleeding. 378:hypertensive crisis 310:signal transduction 287:Mechanism of action 208:monoclonal antibody 106:autophosphorylation 1795:Annals of Oncology 1687:Annals of Oncology 1012: 910: 897: 882: 866:fibrotic disorders 832:anti-proliferation 825: 787: 785:Indolin structure. 762: 704: 686: 592:ABCG2 transporters 430:skin discoloration 420:, abdominal pain, 390:nephrotic syndrome 332:or VEGF receptor. 138:-like domain. The 44:and angiogenesis. 34:signaling pathways 2258:www.ema.europa.eu 2171:www.ema.europa.eu 2142:www.ema.europa.eu 2113:www.ema.europa.eu 2084:www.ema.europa.eu 2055:www.ema.europa.eu 2026:www.ema.europa.eu 1857:(11): 1817–1828. 1693:(11): 2244–2251. 1312:(12): 1788–1795. 1160:10.1021/ml5004876 1116:10.1021/jm301085w 1060:10.1021/jm701097z 432:, altered taste, 306:dephosphorylation 96:, proliferation, 17:VEGFR-2 inhibitor 2345: 2322: 2321: 2319: 2317: 2302: 2296: 2295: 2293: 2291: 2276: 2270: 2269: 2267: 2265: 2255: 2247: 2241: 2240: 2238: 2236: 2226: 2218: 2212: 2211: 2209: 2207: 2200:www.ec.europa.eu 2197: 2189: 2183: 2182: 2180: 2178: 2168: 2160: 2154: 2153: 2151: 2149: 2139: 2131: 2125: 2124: 2122: 2120: 2110: 2102: 2096: 2095: 2093: 2091: 2081: 2073: 2067: 2066: 2064: 2062: 2052: 2044: 2038: 2037: 2035: 2033: 2023: 2015: 2009: 2008: 1983:(4): 1108–1110. 1972: 1961: 1960: 1942: 1933:(6): S131–S134. 1918: 1912: 1911: 1909: 1907: 1892: 1883: 1882: 1845: 1839: 1838: 1820: 1810: 1785: 1779: 1778: 1768: 1727: 1721: 1720: 1702: 1677: 1668: 1667: 1665: 1663: 1648: 1642: 1641: 1639: 1637: 1627: 1619: 1613: 1612: 1575: 1569: 1568: 1566: 1564: 1557:lskbiopharma.com 1549: 1543: 1542: 1540: 1538: 1531:www.ec.europa.eu 1528: 1520: 1514: 1513: 1511: 1509: 1494: 1488: 1487: 1485: 1483: 1473: 1465: 1459: 1458: 1456: 1454: 1439: 1433: 1432: 1430: 1428: 1418: 1410: 1401: 1400: 1398: 1396: 1386: 1378: 1372: 1371: 1369: 1367: 1357: 1349: 1340: 1339: 1329: 1297: 1262: 1261: 1233: 1182: 1181: 1171: 1139: 1128: 1127: 1099: 1080: 1079: 1054:(6): 1649–1667. 1042: 934:Pharmacokinetics 862:viral infections 805:pharmacokinetics 752:Urea derivatives 453:vasoconstriction 19:, also known as 2353: 2352: 2348: 2347: 2346: 2344: 2343: 2342: 2328: 2327: 2326: 2325: 2315: 2313: 2304: 2303: 2299: 2289: 2287: 2278: 2277: 2273: 2263: 2261: 2253: 2249: 2248: 2244: 2234: 2232: 2224: 2220: 2219: 2215: 2205: 2203: 2195: 2191: 2190: 2186: 2176: 2174: 2166: 2162: 2161: 2157: 2147: 2145: 2137: 2133: 2132: 2128: 2118: 2116: 2108: 2104: 2103: 2099: 2089: 2087: 2079: 2075: 2074: 2070: 2060: 2058: 2050: 2046: 2045: 2041: 2031: 2029: 2021: 2017: 2016: 2012: 1974: 1973: 1964: 1920: 1919: 1915: 1905: 1903: 1894: 1893: 1886: 1847: 1846: 1842: 1787: 1786: 1782: 1729: 1728: 1724: 1679: 1678: 1671: 1661: 1659: 1650: 1649: 1645: 1635: 1633: 1625: 1621: 1620: 1616: 1577: 1576: 1572: 1562: 1560: 1551: 1550: 1546: 1536: 1534: 1526: 1522: 1521: 1517: 1507: 1505: 1496: 1495: 1491: 1481: 1479: 1471: 1467: 1466: 1462: 1452: 1450: 1441: 1440: 1436: 1426: 1424: 1416: 1412: 1411: 1404: 1394: 1392: 1384: 1380: 1379: 1375: 1365: 1363: 1355: 1351: 1350: 1343: 1299: 1298: 1265: 1244:(9): 987–1004. 1235: 1234: 1185: 1141: 1140: 1131: 1101: 1100: 1083: 1044: 1043: 1039: 1034: 1026:clinical trials 1021: 1004: 995: 982: 968: 952:protein binding 941: 936: 931: 902: 874: 817: 779: 760:Urea structure. 754: 696: 691: 648: 564: 543:Hyperthyroidism 525:cerebral oedema 488:bowel resection 323:adverse effects 319: 317:Adverse Effects 298:internalization 289: 206:is a humanized 160:phosphorylation 152: 134:signal and a 7 127: 119:medulloblastoma 70: 50: 12: 11: 5: 2351: 2349: 2341: 2340: 2330: 2329: 2324: 2323: 2297: 2271: 2242: 2213: 2184: 2155: 2126: 2097: 2068: 2039: 2010: 1962: 1913: 1884: 1840: 1801:(2): 529–536. 1780: 1722: 1669: 1643: 1614: 1570: 1544: 1515: 1489: 1460: 1434: 1402: 1373: 1341: 1263: 1183: 1154:(5): 507–512. 1129: 1081: 1036: 1035: 1033: 1030: 1020: 1017: 1003: 1000: 994: 991: 981: 978: 967: 964: 940: 937: 935: 932: 930: 927: 901: 898: 873: 870: 816: 813: 778: 775: 753: 750: 715:, VEGFR-2 and 695: 692: 690: 687: 647: 646:Pipeline drugs 644: 588:P-glycoprotein 563: 560: 555:adrenal cortex 461:blood pressure 459:and increased 318: 315: 288: 285: 284: 283: 277: 267: 261: 251: 241: 231: 201: 183: 151: 148: 136:immunoglobulin 126: 123: 69: 66: 49: 46: 13: 10: 9: 6: 4: 3: 2: 2350: 2339: 2336: 2335: 2333: 2311: 2310:www.drugs.com 2307: 2301: 2298: 2285: 2284:www.drugs.com 2281: 2275: 2272: 2259: 2252: 2246: 2243: 2230: 2223: 2217: 2214: 2201: 2194: 2188: 2185: 2172: 2165: 2159: 2156: 2143: 2136: 2130: 2127: 2114: 2107: 2101: 2098: 2085: 2078: 2072: 2069: 2056: 2049: 2043: 2040: 2027: 2020: 2014: 2011: 2006: 2002: 1998: 1994: 1990: 1986: 1982: 1978: 1971: 1969: 1967: 1963: 1958: 1954: 1950: 1946: 1941: 1936: 1932: 1928: 1924: 1917: 1914: 1902:. AstraZeneca 1901: 1897: 1891: 1889: 1885: 1880: 1876: 1872: 1868: 1864: 1860: 1856: 1852: 1844: 1841: 1836: 1832: 1828: 1824: 1819: 1814: 1809: 1804: 1800: 1796: 1792: 1784: 1781: 1776: 1772: 1767: 1762: 1758: 1754: 1750: 1746: 1742: 1738: 1734: 1726: 1723: 1718: 1714: 1710: 1706: 1701: 1696: 1692: 1688: 1684: 1676: 1674: 1670: 1657: 1653: 1647: 1644: 1631: 1624: 1618: 1615: 1610: 1606: 1602: 1598: 1594: 1590: 1586: 1582: 1574: 1571: 1558: 1554: 1548: 1545: 1532: 1525: 1519: 1516: 1503: 1499: 1493: 1490: 1477: 1470: 1464: 1461: 1448: 1444: 1438: 1435: 1422: 1415: 1409: 1407: 1403: 1390: 1383: 1377: 1374: 1361: 1354: 1348: 1346: 1342: 1337: 1333: 1328: 1323: 1319: 1315: 1311: 1307: 1303: 1296: 1294: 1292: 1290: 1288: 1286: 1284: 1282: 1280: 1278: 1276: 1274: 1272: 1270: 1268: 1264: 1259: 1255: 1251: 1247: 1243: 1239: 1232: 1230: 1228: 1226: 1224: 1222: 1220: 1218: 1216: 1214: 1212: 1210: 1208: 1206: 1204: 1202: 1200: 1198: 1196: 1194: 1192: 1190: 1188: 1184: 1179: 1175: 1170: 1165: 1161: 1157: 1153: 1149: 1145: 1138: 1136: 1134: 1130: 1125: 1121: 1117: 1113: 1109: 1105: 1098: 1096: 1094: 1092: 1090: 1088: 1086: 1082: 1077: 1073: 1069: 1065: 1061: 1057: 1053: 1049: 1041: 1038: 1031: 1029: 1027: 1018: 1016: 1008: 1001: 999: 992: 990: 987: 979: 977: 974: 965: 963: 961: 957: 953: 949: 945: 938: 933: 928: 926: 923: 917: 915: 906: 899: 893: 889: 885: 878: 871: 869: 867: 863: 859: 855: 851: 846: 842: 837: 833: 828: 821: 814: 812: 810: 806: 801: 798:moiety and a 796: 790: 783: 776: 774: 772: 768: 758: 751: 749: 747: 743: 739: 735: 734:aromatic ring 731: 727: 722: 718: 714: 710: 700: 693: 688: 682: 678: 675: 670: 665: 661: 656: 652: 645: 643: 640: 636: 632: 628: 624: 620: 616: 612: 608: 604: 600: 595: 593: 589: 585: 581: 577: 573: 569: 561: 559: 556: 552: 548: 544: 540: 536: 534: 530: 526: 521: 519: 515: 511: 510:phospholipids 508: 507:pro-coagulant 503: 499: 495: 493: 489: 485: 481: 477: 474: 472: 468: 464: 462: 458: 454: 448: 446: 442: 437: 435: 431: 427: 423: 419: 415: 411: 407: 401: 399: 395: 394:heart failure 391: 387: 383: 379: 375: 371: 367: 363: 359: 355: 351: 347: 343: 339: 333: 330: 326: 324: 316: 314: 311: 307: 303: 299: 295: 286: 281: 278: 275: 271: 268: 265: 262: 259: 256:has the same 255: 252: 249: 245: 242: 239: 235: 232: 229: 225: 221: 217: 213: 209: 205: 202: 199: 195: 191: 187: 184: 181: 177: 173: 169: 165: 161: 157: 154: 153: 149: 147: 145: 141: 140:intracellular 137: 133: 124: 122: 120: 116: 112: 107: 103: 99: 95: 91: 87: 83: 79: 76:expressed in 75: 67: 65: 63: 59: 55: 54:VEGF receptor 47: 45: 43: 39: 38:proliferation 35: 30: 26: 22: 18: 2316:30 September 2314:. Retrieved 2309: 2300: 2290:30 September 2288:. Retrieved 2283: 2274: 2264:26 September 2262:. Retrieved 2257: 2245: 2235:27 September 2233:. Retrieved 2228: 2216: 2206:27 September 2204:. Retrieved 2199: 2187: 2177:27 September 2175:. Retrieved 2170: 2158: 2148:27 September 2146:. Retrieved 2141: 2129: 2119:28 September 2117:. Retrieved 2112: 2100: 2090:28 September 2088:. Retrieved 2083: 2071: 2061:28 September 2059:. Retrieved 2054: 2042: 2032:28 September 2030:. Retrieved 2025: 2013: 1980: 1976: 1930: 1926: 1916: 1906:28 September 1904:. Retrieved 1899: 1854: 1850: 1843: 1798: 1794: 1783: 1743:(1): 35–42. 1740: 1736: 1725: 1690: 1686: 1662:20 September 1660:. Retrieved 1655: 1646: 1636:20 September 1634:. Retrieved 1629: 1617: 1587:(1): 52–66. 1584: 1580: 1573: 1563:27 September 1561:. Retrieved 1556: 1547: 1537:27 September 1535:. Retrieved 1530: 1518: 1508:25 September 1506:. Retrieved 1501: 1492: 1482:20 September 1480:. Retrieved 1475: 1463: 1453:20 September 1451:. 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Drugs.com 2077:"CABOMETYX" 1818:2318/150328 1469:"CABOMETYX" 738:hydrophobic 721:Quinoxaline 607:doxorubicin 498:Haemorrhage 492:anastomosis 486:as well as 484:diverticula 467:Proteinuria 386:haemorrhage 382:neutropenia 346:proteinuria 302:degradation 264:Regorafenib 228:carboplatin 204:Bevacizumab 2251:"Votrient" 2193:"Vargatef" 2106:"Stivarga" 2048:"Caprelsa" 1524:"Vargatef" 1504:. Medscape 1447:Accessdata 1414:"VOTRIENT" 1382:"CAPRELSA" 1032:References 944:Absorption 922:antifungal 655:fibroblast 631:rifampicin 611:irinotecan 529:vasospasms 502:thrombosis 471:glomerular 445:leukopenia 441:dermatitis 434:stomatitis 370:dermatitis 354:stomatitis 270:Nintedanib 258:indication 238:vandetanib 234:Lenvatinib 224:paclitaxel 168:RAF kinase 144:C-terminus 132:N-terminus 84:and binds 42:metastasis 2135:"Nexavar" 2019:"Lenvima" 1997:0960-894X 1949:1556-0864 1871:0090-9556 1827:0923-7534 1757:1522-8002 1709:0923-7534 1623:"NEXAVAR" 1601:1078-1552 1353:"LENVIMA" 1068:0022-2623 960:half-life 736:can form 719:process. 674:Cediranib 669:cytotoxic 664:Vatalanib 660:Motesanib 651:Lucitanib 603:docetaxel 551:pituitary 547:capillary 418:dyspepsia 342:epistaxis 244:Pazopanib 186:Sunitinib 156:Sorafenib 125:Structure 102:migration 90:regulator 2332:Category 2222:"Inlyta" 2164:"Sutent" 2005:24456902 1957:18520296 1879:16882767 1835:24419239 1775:27988457 1717:25193991 1658:. Pfizer 1652:"INLYTA" 1609:24403097 1443:"INLYTA" 1336:17519900 1258:28621580 1178:26005523 1124:23098265 1076:18324761 845:fluorine 809:toxicity 795:oligomer 726:scaffold 619:neomycin 410:diarrhea 406:asthenia 358:diarrhea 280:Apatinib 248:axitinib 182:(NSCLC). 115:melanoma 98:invasion 1766:5167242 1327:2359962 1169:4434476 1019:History 800:pyrrole 742:Asp1046 717:mitosis 635:CYP2C19 366:fatigue 362:dyspnea 304:and by 111:thyroid 80:and in 68:VEGFR-2 2003: 1995: 1955: 1947: 1877: 1869: 1833: 1825: 1773: 1763: 1755: 1715: 1707: 1656:Pfizer 1607: 1599: 1334: 1324: 1256: 1176: 1166: 1122: 1074: 1066: 956:CYP450 836:sulfur 746:Glu885 730:Cys919 639:CYP2D6 627:CYP2C8 623:CYP2B6 576:UGT1A4 572:UGT1A1 514:matrix 414:nausea 220:rectum 164:PDGFRβ 146:tail. 86:VEGF-A 2254:(PDF) 2225:(PDF) 2196:(PDF) 2167:(PDF) 2138:(PDF) 2109:(PDF) 2080:(PDF) 2051:(PDF) 2022:(PDF) 1626:(PDF) 1527:(PDF) 1472:(PDF) 1417:(PDF) 1385:(PDF) 1356:(PDF) 841:c-Met 713:HER-2 568:CYP3A 216:colon 190:CSF1R 48:VEGFR 2318:2018 2292:2018 2266:2018 2237:2018 2208:2018 2179:2018 2150:2018 2121:2018 2092:2018 2063:2018 2034:2018 2001:PMID 1993:ISSN 1953:PMID 1945:ISSN 1908:2018 1875:PMID 1867:ISSN 1831:PMID 1823:ISSN 1771:PMID 1753:ISSN 1713:PMID 1705:ISSN 1664:2018 1638:2018 1605:PMID 1597:ISSN 1565:2018 1539:2018 1510:2018 1484:2018 1455:2018 1429:2018 1397:2018 1368:2018 1332:PMID 1254:PMID 1174:PMID 1120:PMID 1072:PMID 1064:ISSN 948:tmax 864:and 771:IC50 709:EGFR 625:and 617:and 609:and 590:and 584:OAT3 582:and 580:OAT1 574:and 500:and 490:and 396:and 368:and 246:and 236:and 226:and 194:GDNF 192:and 117:and 100:and 52:The 2229:EMA 1985:doi 1935:doi 1859:doi 1813:hdl 1803:doi 1761:PMC 1745:doi 1695:doi 1630:FDA 1589:doi 1476:FDA 1421:FDA 1389:FDA 1360:FDA 1322:PMC 1314:doi 1246:doi 1164:PMC 1156:doi 1112:doi 1056:doi 601:of 599:AUC 329:FDA 218:or 162:), 2334:: 2308:. 2282:. 2256:. 2227:. 2198:. 2169:. 2140:. 2111:. 2082:. 2053:. 2024:. 1999:. 1991:. 1981:24 1979:. 1965:^ 1951:. 1943:. 1929:. 1925:. 1898:. 1887:^ 1873:. 1865:. 1855:34 1853:. 1829:. 1821:. 1811:. 1799:25 1797:. 1793:. 1769:. 1759:. 1751:. 1741:19 1739:. 1735:. 1711:. 1703:. 1691:25 1689:. 1685:. 1672:^ 1654:. 1628:. 1603:. 1595:. 1585:21 1583:. 1555:. 1529:. 1500:. 1474:. 1445:. 1419:. 1405:^ 1387:. 1358:. 1344:^ 1330:. 1320:. 1310:96 1308:. 1304:. 1266:^ 1252:. 1242:27 1240:. 1186:^ 1172:. 1162:. 1150:. 1146:. 1132:^ 1118:. 1108:55 1106:. 1084:^ 1070:. 1062:. 1052:51 1050:. 916:. 868:. 860:, 856:, 852:, 711:, 637:, 605:, 553:, 527:, 428:, 424:, 416:, 412:, 408:, 400:. 392:, 388:, 380:, 364:, 356:, 352:, 348:, 344:, 340:, 300:, 121:. 113:, 40:, 2320:. 2294:. 2268:. 2239:. 2210:. 2181:. 2152:. 2123:. 2094:. 2065:. 2036:. 2007:. 1987:: 1959:. 1937:: 1931:3 1910:. 1881:. 1861:: 1837:. 1815:: 1805:: 1777:. 1747:: 1719:. 1697:: 1666:. 1640:. 1611:. 1591:: 1567:. 1541:. 1512:. 1486:. 1457:. 1431:. 1399:. 1370:. 1338:. 1316:: 1260:. 1248:: 1180:. 1158:: 1152:6 1126:. 1114:: 1078:. 1058:: 200:.

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