Vatalanib

Vatalanib
Clinical data
Pregnancy; category	None assigned;
Routes of; administration	Oral
ATC code	none;
Legal status
Legal status	Investigational;
Pharmacokinetic data
Bioavailability	High
Metabolism	Extensive hepatic metabolism (mostly CYP3A4-mediated)
Elimination half-life	4.6 ± 1.1 h
Excretion	Fecal and renal
Identifiers
	IUPAC name N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin- 1-amine;
CAS Number	212141-54-3;
PubChem CID	151194;
IUPHAR/BPS	5705;
DrugBank	DB04879;
ChemSpider	133257;
UNII	5DX9U76296;
ChEBI	CHEBI:90620;
ChEMBL	ChEMBL101253;
CompTox Dashboard (EPA)	DTXSID2046919 ;
Chemical and physical data
Formula	C20H15ClN4
Molar mass	346.82 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES Clc1ccc(cc1)Nc3nnc(c2c3cccc2)Cc4ccncc4;
	InChI InChI=1S/C20H15ClN4/c21-15-5-7-16(8-6-15)23-20-18-4-2-1-3-17(18)19(24-25-20)13-14-9-11-22-12-10-14/h1-12H,13H2,(H,23,25) ; Key:YCOYDOIWSSHVCK-UHFFFAOYSA-N ;

Vatalanib (INN, codenamed PTK787 or PTK/ZK) is a small molecule protein kinase inhibitor that inhibits angiogenesis. It is being studied as a possible treatment for several types of cancer, particularly cancer that is at an advanced stage or has not responded to chemotherapy. Vatalanib is orally active, which is to say it is effective when taken by mouth.

Vatalanib is being developed by Bayer Schering and Novartis. It inhibits all known VEGF receptors, as well as platelet-derived growth factor receptor-beta and c-kit, but is most selective for VEGFR-2.^[1]^[2]^[3]^[4]

Development

Vatalanib was discovered through high-throughput screening.^[2] It has been extensively investigated in Phase I, II and III clinical trials.^[1]^[4] Two large, randomized controlled Phase III trials have studied the effect of adding vatalanib to the FOLFOX chemotherapy regimen in people with metastatic colorectal cancer: CONFIRM-1, whose participants had not yet received any treatment for their cancer; and CONFIRM-2, in which participants had received first-line treatment with irinotecan and fluoropyrimidines. Vatalanib produced no significant improvement in overall survival (the primary endpoint of the studies), although it did significantly increase progression-free survival in CONFIRM-2.^[4] Both trials found that progression-free survival was improved in people with high levels of lactate dehydrogenase, an enzyme used as a marker of tissue breakdown; the reasons for and implications of this difference are still unclear.^[4]^[5]

Adverse effects

The adverse effects of vatalanib appear similar to those of other VEGF inhibitors. In the CONFIRM trials, the most common side effects were high blood pressure, gastrointestinal upset (diarrhea, nausea, and vomiting), fatigue, and dizziness.^[4]

Notable users

Patrick Swayze, a popular actor in the 1980s who starred in such films as Dirty Dancing and Road House was given this drug when he was diagnosed with Stage IV Pancreatic Cancer in 2008. Doctors hoped the drug would cut off blood supply to the tumor.^[6] Despite this, Swayze died on September 14, 2009, 20 months after being diagnosed.^{[citation needed]}

References

^ ^a ^b ^c ^d ^e Jost LM, Gschwind HP, Jalava T, et al. (November 2006). "Metabolism and disposition of vatalanib (PTK787/ZK-222584) in cancer patients". Drug Metabolism and Disposition. 34 (11): 1817–28. doi:10.1124/dmd.106.009944. PMID 16882767. S2CID 9545358.
^ ^a ^b Mariani SM (2004). "Antiangiogenesis Cocktails -- Stirred or Shaken?: Highlights of the 9th Annual Drug Discovery Technology World Congress; August 8-13, 2004; Boston, Massachusetts". Medscape General Medicine. 6 (4): 21. PMC 1480579. PMID 15775848. Retrieved on October 29, 2008.
^ Wood JM, Bold G, Buchdunger E, et al. (April 2000). "PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration". Cancer Research. 60 (8): 2178–89. PMID 10786682.
^ ^a ^b ^c ^d ^e Los M, Roodhart JM, Voest EE (April 2007). "Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer". The Oncologist. 12 (4): 443–50. doi:10.1634/theoncologist.12-4-443. PMID 17470687.
^ Scott EN, Meinhardt G, Jacques C, Laurent D, Thomas AL (March 2007). "Vatalanib: the clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours". Expert Opin Investig Drugs. 16 (3): 367–79. doi:10.1517/13543784.16.3.367. PMID 17302531. S2CID 41568265.
^ Mann, Denise. "Patrick Swayze Dies of Pancreatic Cancer". WebMD. Retrieved 3 April 2021.

External links

Ongoing and completed clinical trials of vatalanib at ClinicalTrials.gov (U.S. National Institutes of Health)

[Jost-1] Jost LM, Gschwind HP, Jalava T, et al. (November 2006). "Metabolism and disposition of vatalanib (PTK787/ZK-222584) in cancer patients". Drug Metabolism and Disposition. 34 (11): 1817–28. doi:10.1124/dmd.106.009944. PMID 16882767. S2CID 9545358.

[Mariani-2] Mariani SM (2004). "Antiangiogenesis Cocktails -- Stirred or Shaken?: Highlights of the 9th Annual Drug Discovery Technology World Congress; August 8-13, 2004; Boston, Massachusetts". Medscape General Medicine. 6 (4): 21. PMC 1480579. PMID 15775848. Retrieved on October 29, 2008.

[Wood-3] Wood JM, Bold G, Buchdunger E, et al. (April 2000). "PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration". Cancer Research. 60 (8): 2178–89. PMID 10786682.

[Los-4] Los M, Roodhart JM, Voest EE (April 2007). "Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer". The Oncologist. 12 (4): 443–50. doi:10.1634/theoncologist.12-4-443. PMID 17470687.

[5] Scott EN, Meinhardt G, Jacques C, Laurent D, Thomas AL (March 2007). "Vatalanib: the clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours". Expert Opin Investig Drugs. 16 (3): 367–79. doi:10.1517/13543784.16.3.367. PMID 17302531. S2CID 41568265.

[6] Mann, Denise. "Patrick Swayze Dies of Pancreatic Cancer". WebMD. Retrieved 3 April 2021.

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