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Identification
NameVismodegib
Accession NumberDB08828
TypeSmall Molecule
GroupsApproved
Description

Vismodegib inhibits the hedgehog signalling pathway and is indicated for treatment of adult basal cell carcinoma. FDA approved on Jan 30, 2012.

Structure
Thumb
Synonyms
Erivedge
GDC-0449
Hedgehog Antagonist GDC-0449
Vismodegibum
External Identifiers
  • RG-3616
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Erivedgecapsule150 mg/1oralGenentech, Inc.2012-01-30Not applicableUs
Erivedgecapsule150 mgoralHoffmann La Roche Limited2013-08-09Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII25X868M3DS
CAS number879085-55-9
WeightAverage: 421.297
Monoisotopic: 420.010218428
Chemical FormulaC19H14Cl2N2O3S
InChI KeyInChIKey=BPQMGSKTAYIVFO-UHFFFAOYSA-N
InChI
InChI=1S/C19H14Cl2N2O3S/c1-27(25,26)13-6-7-14(17(21)11-13)19(24)23-12-5-8-16(20)15(10-12)18-4-2-3-9-22-18/h2-11H,1H3,(H,23,24)
IUPAC Name
2-chloro-N-[4-chloro-3-(pyridin-2-yl)phenyl]-4-methanesulfonylbenzamide
SMILES
CS(=O)(=O)C1=CC(Cl)=C(C=C1)C(=O)NC1=CC=C(Cl)C(=C1)C1=CC=CC=N1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as n-phenylbenzamides. These are benzamides that are N-linked to a phenyl group via the carboxamide group.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassBenzamides
Direct ParentN-phenylbenzamides
Alternative Parents
Substituents
  • N-phenylbenzamide
  • 2-phenylpyridine
  • N-arylamide
  • Halobenzoic acid or derivatives
  • 2-halobenzoic acid or derivatives
  • Benzoic acid or derivatives
  • Benzoyl
  • Halobenzene
  • Chlorobenzene
  • Pyridine
  • Aryl halide
  • Aryl chloride
  • Heteroaromatic compound
  • Vinylogous halide
  • Sulfonyl
  • Sulfone
  • Secondary carboxylic acid amide
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organosulfur compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Carbonyl group
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationVismodegib is used for treating locally advanced or metastatic basal cell carcinoma in patients whose carcinoma has recurred after surgery, and in patients who are not candidates for surgery or radiation.
PharmacodynamicsVismodegib selectively binds to and inhibits the transmembrane protein Smoothened homologue (SMO) to inhibit the Hedgehog signalling pathway.
Mechanism of actionMutations of the Hedgehog pathway may results in uncontrolled proliferation of skin basal cells. Vismodegib binds to and inhibits the transmembrane protein Smoothened homologue (SMO) to inhibit the Hedgehog signalling pathway.
Related Articles
AbsorptionThe absolute bioavailability of a single dose is 31.8%. Absorption is saturable and is not affected by food.
Volume of distribution

Vismodegib has a volume of distribution of 16.4 to 26.6 L.

Protein bindingVismodegib is highly protein bound with plasma protein binding at about 99%. Vismodegib binds to the plasma proteins, albumin and alpha-1-acid glycoprotein (saturable bnding).
Metabolism

The main metabolic enzymes are CYP2C9 and CYP3A4, however more than 98% of total systemic vismodegib is not metabolized. Metabolic pathways of vismodegib in humans include oxidation, glucuronidation, and pyridine ring cleavage. The two most abundant oxidative metabolites recovered in feces are produced in vitro by recombinant CYP2C9 and CYP3A4/5.

Route of eliminationVismodegib is mostly excreted unchanged, and the main route of elimination is by the feces (82%) and the urine accounts for 4.4%.
Half lifeThe half-life after a single dose is 12 days, and after continuous daily dosing is 4 days.
ClearanceNot Available
ToxicityIncreased risk of embryo-fetal death and significant birth defects. Common adverse event include muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9547
Blood Brain Barrier+0.9387
Caco-2 permeable+0.6048
P-glycoprotein substrateNon-substrate0.8443
P-glycoprotein inhibitor INon-inhibitor0.8663
P-glycoprotein inhibitor IINon-inhibitor0.9558
Renal organic cation transporterNon-inhibitor0.8925
CYP450 2C9 substrateNon-substrate0.6009
CYP450 2D6 substrateNon-substrate0.63
CYP450 3A4 substrateNon-substrate0.5083
CYP450 1A2 substrateNon-inhibitor0.6067
CYP450 2C9 inhibitorInhibitor0.9078
CYP450 2D6 inhibitorNon-inhibitor0.6638
CYP450 2C19 inhibitorInhibitor0.8515
CYP450 3A4 inhibitorInhibitor0.8452
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9282
Ames testNon AMES toxic0.8271
CarcinogenicityNon-carcinogens0.6746
BiodegradationNot ready biodegradable0.9956
Rat acute toxicity2.0840 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9973
hERG inhibition (predictor II)Non-inhibitor0.8224
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Capsuleoral150 mg/1
Capsuleoral150 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7888364 No2008-11-112028-11-11Us
US9278961 No2008-12-152028-12-15Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubility0.1 μg/mL and is pH dependent FDA label
logP2.7 FDA label
pKa3.8FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.00173 mg/mLALOGPS
logP4.22ALOGPS
logP3.93ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)10.27ChemAxon
pKa (Strongest Basic)3.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area76.13 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity107.81 m3·mol-1ChemAxon
Polarizability39.49 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Mackey HM, Lum BL, Darbonne WC, Marsters JC Jr, de Sauvage FJ, Low JA: Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009 Sep 17;361(12):1164-72. doi: 10.1056/NEJMoa0905360. Epub 2009 Sep 2. [PubMed:19726763 ]
  2. Sandhiya S, Melvin G, Kumar SS, Dkhar SA: The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7. doi: 10.4103/0976-500X.107628. [PubMed:23662017 ]
External Links
ATC CodesL01XX43
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelDownload (211 KB)
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Wnt-protein binding
Specific Function:
G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7 and GLI3 in the cilia.
Gene Name:
SMO
Uniprot ID:
Q99835
Molecular Weight:
86395.95 Da
References
  1. Sandhiya S, Melvin G, Kumar SS, Dkhar SA: The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7. doi: 10.4103/0976-500X.107628. [PubMed:23662017 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
no
Actions
substrateinhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular Weight:
55627.365 Da
References
  1. Sandhiya S, Melvin G, Kumar SS, Dkhar SA: The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7. doi: 10.4103/0976-500X.107628. [PubMed:23662017 ]
Kind
Protein
Organism
Human
Pharmacological action
no
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Sandhiya S, Melvin G, Kumar SS, Dkhar SA: The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7. doi: 10.4103/0976-500X.107628. [PubMed:23662017 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme...
Gene Name:
CYP2C8
Uniprot ID:
P10632
Molecular Weight:
55824.275 Da
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine.
Gene Name:
CYP2C19
Uniprot ID:
P33261
Molecular Weight:
55930.545 Da

Carriers

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Toxic substance binding
Specific Function:
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.
Gene Name:
ALB
Uniprot ID:
P02768
Molecular Weight:
69365.94 Da
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Not Available
Specific Function:
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction.
Gene Name:
ORM1
Uniprot ID:
P02763
Molecular Weight:
23511.38 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
References
  1. Sandhiya S, Melvin G, Kumar SS, Dkhar SA: The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013 Jan;4(1):4-7. doi: 10.4103/0976-500X.107628. [PubMed:23662017 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from t...
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
Molecular Weight:
72313.47 Da
Comments
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Drug created on January 04, 2013 14:48 / Updated on July 23, 2016 02:29