4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide

• ChemBase ID: 281
• Molecular Formular: C21H16ClF3N4O3
• Molecular Mass: 464.8249496
• Monoisotopic Mass: 464.08630273
• SMILES: Clc1c(cc(NC(=O)Nc2ccc(Oc3cc(ncc3)C(=O)NC)cc2)cc1)C(F)(F)F
• Canonical SMILES: CNC(=O)c1nccc(c1)Oc1ccc(cc1)NC(=O)Nc1ccc(c(c1)C(F)(F)F)Cl
• InChI: InChI=1S/C21H16ClF3N4O3/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,28,29,31)
• InChIKey: MLDQJTXFUGDVEO-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide
• IUPAC Traditional name: sorafenib tosylate; 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide; sorafenib
• Brand Name: Nexavar
• Synonyms: 4-{4-[({[4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL]AMINO}CARBONYL)AMINO]PHENOXY}-N-METHYLPYRIDINE-2-CARBOXAMIDE; BAY 43-9006; Sorafenib tosylate; sorafenib; Sorafenib; Nexavar; Sorafenib; 4-[4-[[[[4-Chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide; BAY-43-9006; Sorafenib tosylate

Database IDs

• CAS Number: 4750207-59-1; 284461-73-0; 284461-73-0
• PubChem SID: 160963744; 46505329
• PubChem CID: 216239

CALCULATED PROPERTIES

JChem

• Acid pKa: 11.549798
• H Acceptors: 3
• H Donor: 3
• LogD (pH = 5.5): 4.3431873
• LogD (pH = 7.4): 4.343299
• Log P: 4.34333
• Molar Refractivity: 114.5183 cm^3
• Polarizability: 41.29006 Å^3
• Polar Surface Area: 92.35 Å^2
• Rotatable Bonds: 6
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 4.12
• LOG S: -5.43
• Solubility (Water): 1.71e-03 g/l

PROPERTIES

Physical Property

• Solubility: DMSO; Methanol; Practically insoluble (as tosylate salt)
• Apperance: Light Yellow Solid
• Melting Point: 202-204°C
• Hydrophobicity(logP): 3.8

Safety Information

• Storage Condition: -20°C Freezer

Pharmacology Properties

• Target: Raf
• Mechanism of Action: Inhibitor of Raf kinase; PDGF (platelet-derived growth factor); VEGF receptor 2 & 3 kinases and c Kit the receptor for Stem cell factor

Product Information

• Purity: 93%
• Salt Data: Free Base
• Application(s): Drug for the treatment of advanced renal cell carcinoma (primary kidney cancer)

DETAILS

DrugBank - DB07438

Drug information: experimental

DrugBank - DB00398

• Drug Groups: approved; investigational
• Description: Sorafenib (rINN), marketed as Nexavar by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer). It has also received "Fast Track" designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer), and has since performed well in Phase III trials.; Sorafenib is a small molecular inhibitor of Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 & 3 kinases and c Kit the receptor for Stem cell factor. A growing number of drugs target most of these pathways. The originality of Sorafenib lays in its simultaneous targeting of the Raf/Mek/Erk pathway.
• Indication: For the treatment of patients with advanced renal cell carcinoma.
• Pharmacology: Sorafenib is a multikinase inhibitor targeting several serine/threonine and receptor tyrosine kinases. It is commonly available as a tosylate salt. Sorafenib is a multikinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib inhibits tumor growth of the murine renal cell carcinoma, RENCA, and several other human tumor xenografts in athymic mice. A reduction in tumor angiogenesis occurs in some tumor xenograft models.
• Toxicity: The highest dose of sorafenib studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhea and dermatologic events. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals.
• Affected Organisms: Humans and other mammals
• Biotransformation: Sorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady- state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes at steady-state.
• Absorption: The mean relative bioavailability is 38-49% for the tablet form, when compared to an oral solution. With a high-fat meal, bioavailability is reduced by 29% compared to administration in the fasted state.
• Half Life: 25-48 hours
• Protein Binding: 99.5%
• Elimination: Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces, and 19% of the dose excreted in urine as glucuronidated metabolites.
• External Links: Wikipedia; Drugs.com

Toronto Research Chemicals - S676850

Multiple kinase inhibitor targeting both RAF kinase and receptor tyrosine kinases that promote angiogensis. Antineoplastic.

REFERENCES

• Richly, H., et al.: Int. J. Clin. Pharmacol. Ther., 41, 620 (2003)
• Khire, U.R., et al.: Bioorg. Med. Chem. Lett., 14, 783 (2003)
• Wilhelm, S.M., et al.: Cancer Res., 64, 7099 (2003)
• Rini, B.I., et al.: Expert Opin. Pharmacother., 7, 453 (2003)