N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine

• ChemBase ID: 202
• Molecular Formular: C22H24ClFN4O3
• Molecular Mass: 446.9023632
• Monoisotopic Mass: 446.15209655
• SMILES: Clc1cc(Nc2ncnc3c2cc(OCCCN2CCOCC2)c(OC)c3)ccc1F
• Canonical SMILES: COc1cc2ncnc(c2cc1OCCCN1CCOCC1)Nc1ccc(c(c1)Cl)F
• InChI: InChI=1S/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4,11-14H,2,5-10H2,1H3,(H,25,26,27)
• InChIKey: XGALLCVXEZPNRQ-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine
• IUPAC Traditional name: gefitinib; N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine
• Brand Name: Iressa; Irressat; Tarceva
• Synonyms: N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4-quinazolinamine; ZD 1839; N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine; Iressa; Gefitinib(Iressa); ZD1839; ZD-1839; Gefitinib; Irressat; Tarceva; Gefitinib

Database IDs

• CAS Number: 184475-35-2
• MDL Number: MFCD04307832
• PubChem SID: 160963665; 46508649
• PubChem CID: 123631

CALCULATED PROPERTIES

JChem

• Acid pKa: 16.105064
• H Acceptors: 7
• H Donor: 1
• LogD (pH = 5.5): 2.3489094
• LogD (pH = 7.4): 3.6437926
• Log P: 3.7509537
• Molar Refractivity: 117.5068 cm^3
• Polarizability: 45.920685 Å^3
• Polar Surface Area: 68.74 Å^2
• Rotatable Bonds: 8
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 4.02
• LOG S: -4.22
• Solubility (Water): 2.70e-02 g/l

PROPERTIES

Physical Property

• Solubility: DMSO; Sparingly soluble (
• Apperance: White to Off-White Solid
• Melting Point: 194-196°C
• Hydrophobicity(logP): 3.2

Safety Information

• Storage Condition: -20°C; -20°C Freezer
• Storage Warning: IRRITANT
• TSCA Listed: false

Pharmacology Properties

• Target: EGFR
• Mechanism of Action: Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme.; It is the first selective inhibitor of epidermal growth factor receptor's (EGFR) tyrosine kinase domain; Thus the function of the EGFR tyrosine kinase in activating the Ras signal transduction cascade is inhibited, and malignant cells are inhibited

Product Information

• Purity: 95+%; 98%
• Salt Data: Free Base
• Application(s): Gefitinib is a drug used in the treatment of certain types of cancer

DETAILS

DrugBank - DB00317

• Drug Groups: approved; investigational
• Description: Gefitinib (originally coded ZD1839) is a drug used in the treatment of certain types of cancer. Acting in a similar manner to erlotinib (marketed as Tarceva), gefitinib selectively targets the mutant proteins in malignant cells. It is marketed by AstraZeneca under the trade name Iressa. [Wikipedia]
• Indication: For the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of either platinum-based or docetaxel chemotherapies.
• Pharmacology: Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells.
• Toxicity: The acute toxicity of gefitinib up to 500 mg in clinical studies has been low. In non-clinical studies, a single dose of 12,000 mg/m^2 (about 80 times the recommended clinical dose on a mg/m^2 basis) was lethal to rats. Half this dose caused no mortality in mice. Symptoms of overdose include diarrhea and skin rash.
• Affected Organisms: Humans and other mammals
• Biotransformation: Primarily hepatic via CYP3A4. Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino-group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group.
• Absorption: Absorbed slowly after oral administration with mean bioavailability of 60%.
• Half Life: 48 hours
• Protein Binding: 90% primarily to serum albumin and alpha 1-acid glycoproteins.
• Elimination: Elimination is by metabolism (primarily CYP3A4) and excretion in feces. Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose.
• Distribution: * 1400 L
• Clearance: * 595 mL/min
• References: Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11. Epub 2004 Aug 25. [Pubmed] ; Sordella R, Bell DW, Haber DA, Settleman J: Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004 Aug 20;305(5687):1163-7. Epub 2004 Jul 29. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1025

Research Area

• Description: Glioblastoma, Bladder cancer

Biological Activity

• Description: Gefitinib (Iressa, ZD-1839) is an EGFR inhibitor for Tyr1173, Tyr992, Tyr1173 and Tyr992 in the NR6wtEGFR and NR6W cells with IC50 of 37 nM, 37nM, 26 nM and 57 nM, respectively.
• Targets: Tyr1173 (NR6wtEGFR cells); Tyr992 (NR6wtEGFR cells); Tyr1173 (NR6W cells); Tyr992 (NR6W cells)
• IC50: 37 nM; 37nM; 26 nM; 57 nM ^[1]
• In Vitro: Gefitinib effectively inhibits all tyrosine phosphorylation sites on EGFR in both the high and low-EGFR-expressing cell lines including NR6, NR6M and NR6W cell lines. The phosphorylation sites Tyr1173 and Tyr992 are less sensitive requiring higher concentrations of Gefitinib for inhibition. Gefitinib effectively blocks the phosphorylation of PLC-γ, with IC50 of 27nM, in NR6W cells. The NR6wtEGFR and NR6M cell lines has low levels of PLC-γ phosphorylation but the level in the NR6M cell line is more resistant to inhibition by Gefitinib with IC50 of 43 nM and 369 nM, respectively. Gefitinib inhibits Akt phosphorylations, with IC50 of 220 and 263nM, in the low-EGFR- and -EGFRvIII-expressing cell lines, respectively. Gefitinib in the dose range from 0.1 to 0.5μM significantly facilitates, rather than abrogates, colony formation of NR6M cells. However, at a concentration of 2 μM Gefitinib completely blocks NR6M colony formation. Gefitinib rapidly and in a dose-dependent manner inhibits EGFR and ERK phosphorylation up to 72 hours after EGF stimulation in both the high- and low-EGFR-expressing cell lines. ^[1] Gefitinib is the monolayer growth of these EGF-driven untransformed MCF10A cells with an IC50 of 20 nM. ^[2] Gefitinib blocks EGF signalling in MDA-MB-231 cells. Gefitinib severely inhibits this increase in cell number in a dose-dependent manner. ^[3]
• In Vivo: Gefitinib inhibits tumour growth of SKOV3 or MDA-MB-231 tumors in athymic nude mice. Gefitinib is effective against both types of tumour. Growth of MDA-MB-231 tumors over the 14-day treatment period is inhibited by approximately 71% and that of SKOV3 tumors by approximately 32%. ^[3] Gefitinib treatment of nude mice bearing established human GEO colon cancer xenografts reveals a reversible dose-dependent inhibition of tumor growth because GEO tumors resumes the growth rate of controls at the end of the treatment. ^[4]
• Clinical Trials: Gefitinib has entered in a phase II clinical trial in the treatment of non small cell lung cancer.
• Features: Gefitinib is a potent EGFR tyrosine kinase inhibitor.

Combination Therapy

• Description: Coadministration of Gefitinib, as with anti-EGFR, will enhance the efficacy of cytotoxic agents against human vulvar (A431), lung (A549 and SK-LC-16 NSCL and LX-1), and prostate (PC-3 and TSU-PR1) tumors. Although Paclitaxel or Docetaxel, as single agents markedly inhibits the growth of A431, LX-1, SK-LC-16, TSU-PR1, and PC-3, when combined with Gefitinib, partial or complete regression is usually seen. Against A549, the growth inhibition of Doxorubicin is increased 10-fold (>99%) with Gefitinib. ^[5]

Protocol

• Protocol: Cell Assay ^[1]
• Cell Lines: NR6, NR6M and NR6W cells
• Concentrations: 0-2 μM
• Incubation Time: 72 hours
• Methods: Exponentially growing cells including NR6, NR6M, NR6M and NR6W cells are seeded in sextuple in 96-well plates at a concentration of 2000 cells/well, allowed to adhere and subsequently washed in PBS and incubated overnight in medium containing 0.5% FCS. Cells are then treated with varying concentrations (0-2 μM) of Gefitinib or the solute control DMSO and EGF. The optimal EGF concentration for inducing proliferation of NR6wtEGFR and NR6W cells has previously been determined and hence NR6wtEGFR and NR6W cells are supplemented with 10 nM and 0.1 nM EGF, respectively. EGF is not added to NR6 and NR6M cells. After 72 hours the amount of cells are measured by performing a MTT proliferation assay.
• Protocol: Animal Study ^[3]
• Animal Models: Athymic nude mice bearing SKOV3 or MDA-MB-231 tumours
• Formulation: 0.2% DMSO
• Doses: 75 mg/kg
• Administration: Gavage

References

• References: [1] Pedersen MW, et al. Br J Cancer. 2005, 93(8), 915-923.
• References: [2] Moasser MM, et al. Cancer Res. 2001, 61(19), 7184-7188.
• References: [3] Anderson NG, et al. Int J Cancer. 2001, 94(6), 774-782.
• References: [4] Ciardiello F, et al. Clin Cancer Res. 2000, 6(5), 2053-2063.
• References: [5] Sirotnak FM, et al. Clin Cancer Res. 2000, 6(12), 4885-4892.

Toronto Research Chemicals - G304000

Gefitinib is an antineoplastic.

REFERENCES

• Sordella R, Bell DW, Haber DA, Settleman J: Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004 Aug 20;305(5687):1163-7. Epub 2004 Jul 29. Pubmed
• Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11. Epub 2004 Aug 25. Pubmed
• Pedersen MW, et al. Br J Cancer. 2005, 93(8), 915-923.
• Moasser MM, et al. Cancer Res. 2001, 61(19), 7184-7188.
• Anderson NG, et al. Int J Cancer. 2001, 94(6), 774-782.
• Ciardiello F, et al. Clin Cancer Res. 2000, 6(5), 2053-2063.
• Sirotnak FM, et al. Clin Cancer Res. 2000, 6(12), 4885-4892.
• Anderson, N.G., et al.: Int. J. Cancer, 94, 774 (2001)
• Hirata, A., et al.: Cancer Res., 62, 2554 (2001)
• Kris, M.G., et al.: J. Am. Med. Assoc., 290, 2149 (2001)
• Tamura, K., et al.: Expert Opin. Pharmacother., 6, 985 (2001)
• 88th Annual Meeting of the American Association for Cancer Research, San Diego, California, USA, 12 -16 April 1997. Lecture, 4251