Vatalanib

Identification

Name
Vatalanib
Accession Number
DB04879
Type
Small Molecule
Groups
Investigational
Description

Vatalanib (PTK787/ZK-222584) is a new oral antiangiogenic molecule that inhibits all known vascular endothelial growth factor receptors. Vatalanib is under investigation for the treatment of solid tumors.

Structure
Thumb
Synonyms
  • 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate
  • PTK 787
  • PTK/ZK
External IDs
CGP 79787 / CGP-797870 / PTK787/ZK 222584 / ZK-232934
Categories
UNII
5DX9U76296
CAS number
212141-54-3
Weight
Average: 346.813
Monoisotopic: 346.098524207
Chemical Formula
C20H15ClN4
InChI Key
YCOYDOIWSSHVCK-UHFFFAOYSA-N
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)
IUPAC Name
N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine
SMILES
ClC1=CC=C(NC2=NN=C(CC3=CC=NC=C3)C3=CC=CC=C23)C=C1

Pharmacology

Indication

Used in combination with first- and second-line chemotherapy for the treatment of metastatic colorectal cancer and non-small cell lung cancer (NSCLC).

Structured Indications
Not Available
Pharmacodynamics

Vatalanib is a novel oral angiogenesis inhibitor being developed by Schering (in collaboration with Novartis AG). Vatalanib selectively inhibits the tyrosine kinase domains of vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor (PDGF) receptor, and c-KIT.

Mechanism of action

Vatalanib potently inhibits vascular endothelial growth factor (VEGF) receptor tyrosine kinases, important enzymes in the formation of new blood vessels that contribute to tumor growth and metastasis.

TargetActionsOrganism
UVascular endothelial growth factor receptor 1Not AvailableHuman
UVascular endothelial growth factor receptor 2Not AvailableHuman
UVascular endothelial growth factor receptor 3Not AvailableHuman
Absorption

Rapid onset of absorption

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Mainly through oxidative metabolism. Two pharmacologically inactive metabolites, CGP 84368/ZK 260120 and NVP AAW378/ZK 261557, having systemic exposure comparable to that of vatalanib, contributed mainly to the total systemic exposure.

Route of elimination
Not Available
Half life

Approximately 6 hours.

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Vatalanib Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Yamamoto A, Watanabe H, Sueki H, Nakanishi T, Yasuhara H, Iijima M: Vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK 222584 inhibits both the induction and elicitation phases of contact hypersensitivity. J Dermatol. 2007 Jul;34(7):419-29. [PubMed:17584317]
  2. Lijnen HR, Van Hoef B, Kemp D, Collen D: Inhibition of vascular endothelial growth factor receptor tyrosine kinases impairs adipose tissue development in mouse models of obesity. Biochim Biophys Acta. 2007 Sep;1770(9):1369-73. Epub 2007 Jun 15. [PubMed:17616257]
  3. Jost LM, Gschwind HP, Jalava T, Wang Y, Guenther C, Souppart C, Rottmann A, Denner K, Waldmeier F, Gross G, Masson E, Laurent D: Metabolism and disposition of vatalanib (PTK787/ZK-222584) in cancer patients. Drug Metab Dispos. 2006 Nov;34(11):1817-28. Epub 2006 Aug 1. [PubMed:16882767]
External Links
PubChem Compound
151194
PubChem Substance
175426883
ChemSpider
133257
BindingDB
4851
ChEBI
90620
ChEMBL
CHEMBL101253
PharmGKB
PA7001

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentGastrinoma / Glucagonoma / Insulinoma / Metastatic Gastrointestinal Carcinoid Tumor / Metastatic Pheochromocytoma / Pancreatic Polypeptide Tumor / Recurrent Gastrointestinal Carcinoid Tumor / Recurrent Islet Cell Carcinoma / Recurrent Melanoma / Recurrent Neuroendocrine Carcinoma of the Skin / Recurrent Non-small Cell Lung Cancer / Recurrent Pheochromocytoma / Recurrent Renal Cell Cancer / Somatostatinoma / Stage III Neuroendocrine Carcinoma of the Skin / Stage IV Melanoma / Stage IV Non-Small Cell Lung Cancer / Stage IV Renal Cell Cancer / Thyroid Gland Medullary Carcinoma / Unspecified Adult Solid Tumor, Protocol Specific1
1Active Not RecruitingTreatmentUnspecified Adult Solid Tumor, Protocol Specific1
1CompletedTreatmentBrain and Central Nervous System Tumors1
1CompletedTreatmentCancer, Breast / Cancer, Ovarian / Cervical Cancers / Endometrial Cancers / Fallopian Tube Cancer / Malignant Peritoneal Neoplasm1
1CompletedTreatmentGlioblastomas1
1CompletedTreatmentRenal Cancers / Unspecified Adult Solid Tumor, Protocol Specific1
1Unknown StatusTreatmentMetastatic Non-hematologic Malignancies1
1, 2CompletedTreatmentAcute Myelogenous Leukaemia (AML) / Agnogenic Myeloid Metaplasia / Chronic Myelogenous Leukemia (CML)1
1, 2CompletedTreatmentBrain and Central Nervous System Tumors1
1, 2CompletedTreatmentMalignant Neoplasm of Pancreas1
1, 2CompletedTreatmentNeoplasms Metastasis / Tumors1
1, 2SuspendedTreatmentMelanoma1
1, 2TerminatedTreatmentProstate Cancer1
2CompletedTreatmentBrain and Central Nervous System Tumors / Sarcomas1
2CompletedTreatmentCentral Nervous System Capillary Hemangioblastoma / CNS Hemangioblastoma / Retinal Capillary Hemangioblastoma / Retinal Hemangioblastoma / Von Hippel-Lindau Disease1
2CompletedTreatmentLeukemias / Myelodysplastic Syndromes / Myelodysplastic/Myeloproliferative Neoplasms1
2CompletedTreatmentMelanoma (Skin)1
2CompletedTreatmentMesothelioma, Malignant1
2CompletedTreatmentMetastatic Neuroendocrine Tumors1
2CompletedTreatmentSarcomas1
2TerminatedTreatmentLymphoma, Large-Cell, Diffuse1
2TerminatedTreatmentMultiple Myeloma (MM)1
2WithdrawnTreatmentCarcinoid tumour of the gastrointestinal tract / Carcinoma, Islet Cell1
3CompletedTreatmentColonic Neoplasms / Neoplasms, Colorectal / Rectal Neoplasms2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00179 mg/mLALOGPS
logP4.5ALOGPS
logP4.15ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)15.17ChemAxon
pKa (Strongest Basic)4.95ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area50.7 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity100.98 m3·mol-1ChemAxon
Polarizability36.52 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.994
Blood Brain Barrier+0.9829
Caco-2 permeable+0.6936
P-glycoprotein substrateNon-substrate0.642
P-glycoprotein inhibitor INon-inhibitor0.8083
P-glycoprotein inhibitor IINon-inhibitor0.8599
Renal organic cation transporterNon-inhibitor0.6742
CYP450 2C9 substrateNon-substrate0.8868
CYP450 2D6 substrateNon-substrate0.8483
CYP450 3A4 substrateNon-substrate0.6173
CYP450 1A2 substrateInhibitor0.9209
CYP450 2C9 inhibitorInhibitor0.637
CYP450 2D6 inhibitorInhibitor0.5654
CYP450 2C19 inhibitorInhibitor0.8432
CYP450 3A4 inhibitorInhibitor0.6922
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8539
Ames testAMES toxic0.5592
CarcinogenicityNon-carcinogens0.803
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.4258 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7061
hERG inhibition (predictor II)Non-inhibitor0.8813
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phthalazines. These are compounds containing a phthalazine moiety, which consists of a benzene ring fused to a pyridazine, forming a 2,3-benzodiazine skeleton.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Benzodiazines
Direct Parent
Phthalazines
Alternative Parents
Aniline and substituted anilines / Chlorobenzenes / Aminopyridazines / Pyridines and derivatives / Imidolactams / Aryl chlorides / Heteroaromatic compounds / Secondary amines / Azacyclic compounds / Organopnictogen compounds
show 2 more
Substituents
Phthalazine / Aniline or substituted anilines / Aminopyridazine / Chlorobenzene / Halobenzene / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Pyridazine / Pyridine
show 13 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Vegf-b-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell ...
Gene Name
FLT1
Uniprot ID
P17948
Uniprot Name
Vascular endothelial growth factor receptor 1
Molecular Weight
150767.185 Da
References
  1. Yamamoto A, Watanabe H, Sueki H, Nakanishi T, Yasuhara H, Iijima M: Vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK 222584 inhibits both the induction and elicitation phases of contact hypersensitivity. J Dermatol. 2007 Jul;34(7):419-29. [PubMed:17584317]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and ...
Gene Name
KDR
Uniprot ID
P35968
Uniprot Name
Vascular endothelial growth factor receptor 2
Molecular Weight
151525.555 Da
References
  1. Yamamoto A, Watanabe H, Sueki H, Nakanishi T, Yasuhara H, Iijima M: Vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK 222584 inhibits both the induction and elicitation phases of contact hypersensitivity. J Dermatol. 2007 Jul;34(7):419-29. [PubMed:17584317]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardi...
Gene Name
FLT4
Uniprot ID
P35916
Uniprot Name
Vascular endothelial growth factor receptor 3
Molecular Weight
152755.94 Da
References
  1. Yamamoto A, Watanabe H, Sueki H, Nakanishi T, Yasuhara H, Iijima M: Vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK 222584 inhibits both the induction and elicitation phases of contact hypersensitivity. J Dermatol. 2007 Jul;34(7):419-29. [PubMed:17584317]

Drug created on October 20, 2007 13:26 / Updated on December 01, 2017 15:33