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IdentificationPharmacologyInteractionsReferencesTrialsEconomicsPropertiesSpectraTaxonomyIdentification
- Name
- Vismodegib
- Accession Number
- DB08828
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Description
Vismodegib inhibits the hedgehog signalling pathway and is indicated for treatment of adult basal cell carcinoma. FDA approved on Jan 30, 2012.
- Structure
Structure for Vismodegib (DB08828)
- Synonyms
- Hedgehog Antagonist GDC-0449
- Vismodegib
- Vismodegibum
- External IDs
- GDC-0449 / RG-3616
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Erivedge Capsule 150 mg/1 Oral Genentech, Inc. 2012-01-30 Not applicable US 
Erivedge Capsule 150 mg Oral Hoffmann La Roche 2013-08-09 Not applicable Canada 
- International/Other Brands
- Erivedge
- Categories
- Amides
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Inhibitors
- Cytochrome P-450 CYP2C19 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Hedgehog Pathway Inhibitor
- P-glycoprotein/ABCB1 Substrates
- Smoothened Receptor Antagonists
- UNII
- 25X868M3DS
- CAS number
- 879085-55-9
- Weight
- Average: 421.297
Monoisotopic: 420.010218428 - Chemical Formula
- C19H14Cl2N2O3S
- InChI Key
- 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
Pharmacology
- Indication
Vismodegib 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.
- Associated Conditions
- Pharmacodynamics
Vismodegib selectively binds to and inhibits the transmembrane protein Smoothened homologue (SMO) to inhibit the Hedgehog signalling pathway.
- Mechanism of action
Mutations 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.
Target Actions Organism ASmoothened homolog antagonistHumans - Absorption
The 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 binding
Vismodegib 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 elimination
Vismodegib is mostly excreted unchanged, and the main route of elimination is by the feces (82%) and the urine accounts for 4.4%.
- Half life
The half-life after a single dose is 12 days, and after continuous daily dosing is 4 days.
- Clearance
- Not Available
- Toxicity
Increased 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
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
Drug Interaction (R)-warfarin The metabolism of (R)-warfarin can be decreased when combined with Vismodegib. (S)-Warfarin The metabolism of (S)-Warfarin can be decreased when combined with Vismodegib. 3,5-diiodothyropropionic acid The metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Vismodegib. 4-hydroxycoumarin The metabolism of 4-hydroxycoumarin can be decreased when combined with Vismodegib. 5-androstenedione The metabolism of Vismodegib can be decreased when combined with 5-androstenedione. 6-Deoxyerythronolide B The metabolism of Vismodegib can be decreased when combined with 6-Deoxyerythronolide B. 6-O-benzylguanine The metabolism of 6-O-benzylguanine can be decreased when combined with Vismodegib. 7-ethyl-10-hydroxycamptothecin The metabolism of Vismodegib can be decreased when combined with 7-ethyl-10-hydroxycamptothecin. 9-aminocamptothecin The metabolism of 9-aminocamptothecin can be decreased when combined with Vismodegib. Abatacept The metabolism of Vismodegib can be increased when combined with Abatacept. - Food Interactions
- Food does not affect absorption.
References
- General References
- 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]
- 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
- KEGG Drug
- D09992
- PubChem Compound
- 24776445
- PubChem Substance
- 175427109
- ChemSpider
- 23337846
- BindingDB
- 50249522
- ChEBI
- 66903
- ChEMBL
- CHEMBL473417
- PharmGKB
- PA166048558
- HET
- VIS
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Vismodegib
- ATC Codes
- L01XX43 — Vismodegib
- AHFS Codes
- 10:00.00 — Antineoplastic Agents
- PDB Entries
- 5l7i
- FDA label
- Download (211 KB)
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Capsule Oral 150 mg/1 Capsule Oral 150 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) US9278961 No 2016-03-08 2028-12-15 US US7888364 No 2011-02-15 2028-11-11 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility 0.1 μg/mL and is pH dependent FDA label logP 2.7 FDA label pKa 3.8 FDA label - Predicted Properties
Property Value Source Water Solubility 0.00173 mg/mL ALOGPS logP 4.22 ALOGPS logP 3.93 ChemAxon logS -5.4 ALOGPS pKa (Strongest Acidic) 10.27 ChemAxon pKa (Strongest Basic) 3.7 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 4 ChemAxon Hydrogen Donor Count 1 ChemAxon Polar Surface Area 76.13 Å2 ChemAxon Rotatable Bond Count 4 ChemAxon Refractivity 107.81 m3·mol-1 ChemAxon Polarizability 39.49 Å3 ChemAxon Number of Rings 3 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
Property Value Probability Human Intestinal Absorption + 0.9547 Blood Brain Barrier + 0.9387 Caco-2 permeable + 0.6048 P-glycoprotein substrate Non-substrate 0.8443 P-glycoprotein inhibitor I Non-inhibitor 0.8663 P-glycoprotein inhibitor II Non-inhibitor 0.9558 Renal organic cation transporter Non-inhibitor 0.8925 CYP450 2C9 substrate Non-substrate 0.6009 CYP450 2D6 substrate Non-substrate 0.63 CYP450 3A4 substrate Non-substrate 0.5083 CYP450 1A2 substrate Non-inhibitor 0.6067 CYP450 2C9 inhibitor Inhibitor 0.9078 CYP450 2D6 inhibitor Non-inhibitor 0.6638 CYP450 2C19 inhibitor Inhibitor 0.8515 CYP450 3A4 inhibitor Inhibitor 0.8452 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.9282 Ames test Non AMES toxic 0.8271 Carcinogenicity Non-carcinogens 0.6746 Biodegradation Not ready biodegradable 0.9956 Rat acute toxicity 2.0840 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9973 hERG inhibition (predictor II) Non-inhibitor 0.8224
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available MS/MS Spectrum - , positive LC-MS/MS splash10-00di-0212900000-190a5fdca2d781122e92
Taxonomy
- Description
- This compound belongs to the class of organic compounds known as benzanilides. These are aromatic compounds containing an anilide group in which the carboxamide group is substituted with a benzene ring. They have the general structure RNC(=O)R', where R,R'= benzene.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Anilides
- Direct Parent
- Benzanilides
- Alternative Parents
- Phenylpyridines / 2-halobenzoic acids and derivatives / Benzamides / Benzenesulfonyl compounds / Benzoyl derivatives / Chlorobenzenes / Aryl chlorides / Vinylogous halides / Sulfones / Heteroaromatic compounds show 8 more
- Substituents
- Benzanilide / 2-phenylpyridine / 2-halobenzoic acid or derivatives / Halobenzoic acid or derivatives / Benzamide / Benzoic acid or derivatives / Benzenesulfonyl group / Benzoyl / Chlorobenzene / Halobenzene show 23 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- sulfone, benzamides, pyridines, monochlorobenzenes (CHEBI:66903)
Targets
- Kind
- Protein
- Organism
- Humans
- 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 t...
- Gene Name
- SMO
- Uniprot ID
- Q99835
- Uniprot Name
- Smoothened homolog
- Molecular Weight
- 86395.95 Da
References
- 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
- Humans
- 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 un...
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- 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]
- Vismodegib FDA Label [File]
- Kind
- Protein
- Organism
- Humans
- 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 react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- 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
- Humans
- 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 un...
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
- Kind
- Protein
- Organism
- Humans
- 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 im...
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55930.545 Da
References
- Fellner C: Vismodegib (erivedge) for advanced Basal cell carcinoma. P T. 2012 Dec;37(12):670-82. [PubMed:23319845]
- Vismodegib [File]
Carriers
- Kind
- Protein
- Organism
- Humans
- 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 colloid...
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Serum albumin
- Molecular Weight
- 69365.94 Da
- Kind
- Protein
- Organism
- Humans
- 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...
- Gene Name
- ORM1
- Uniprot ID
- P02763
- Uniprot Name
- Alpha-1-acid glycoprotein 1
- Molecular Weight
- 23511.38 Da
Transporters
- Kind
- Protein
- Organism
- Humans
- 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
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- 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
- Humans
- 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 fro...
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- ATP-binding cassette sub-family G member 2
- Molecular Weight
- 72313.47 Da
Drug created on January 04, 2013 14:48 / Updated on January 22, 2019 17:56