Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C22H23ClFN5O3.ClH |
| Molecular Weight | 496.362 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
Cl.COC1=C(OC(=O)N2CCN(C)C[C@H]2C)C=C3C(NC4=C(F)C(Cl)=CC=C4)=NC=NC3=C1
InChI
InChIKey=IFVBAZHARMVMRV-BTQNPOSSSA-N
InChI=1S/C22H23ClFN5O3.ClH/c1-13-11-28(2)7-8-29(13)22(30)32-19-9-14-17(10-18(19)31-3)25-12-26-21(14)27-16-6-4-5-15(23)20(16)24;/h4-6,9-10,12-13H,7-8,11H2,1-3H3,(H,25,26,27);1H/t13-;/m1./s1
| Molecular Formula | ClH |
| Molecular Weight | 36.461 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
| Molecular Formula | C22H23ClFN5O3 |
| Molecular Weight | 459.901 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ABSOLUTE |
| Additional Stereochemistry | No |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Optical Activity | UNSPECIFIED |
AZD-3759 is an oral inhibitor of both wild-type and mutant EGFR with IC50 values in nanomolar range. The drug was discovered by AstraZeneca for the treatment of non-small-cell lung cancer with CNS metastases. AZD-3759 can penetrate the blood-brain barrier and was confirmed to be effective in vitro with NSCLC cell lines as well as in mouse model of brain metastases. AZD-3759 is currently in Phase 1 clinical trial.
CNS Activity
Originator
Approval Year
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
326 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30252204 |
10 mg/kg single, oral dose: 10 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
AZD3759 plasma | Rattus norvegicus population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: FASTED |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
4404 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30252204 |
10 mg/kg single, oral dose: 10 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
AZD3759 plasma | Rattus norvegicus population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: FASTED |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
3.5 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30252204 |
10 mg/kg single, oral dose: 10 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
AZD3759 plasma | Rattus norvegicus population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: FASTED |
Overview
| CYP3A4 | CYP2C9 | CYP2D6 | hERG |
|---|---|---|---|
OverviewOther
| Other Inhibitor | Other Substrate | Other Inducer |
|---|---|---|
Drug as perpetrator
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| no [IC50 >50 uM] | ||||
| no [IC50 >50 uM] | ||||
| no [IC50 >50 uM] | ||||
| no [IC50 >50 uM] | ||||
| no [IC50 >50 uM] | ||||
| no [IC50 >50 uM] | ||||
| no [IC50 >50 uM] | ||||
| yes [IC50 1.7 uM] | ||||
| yes [IC50 15 uM] | ||||
| yes [IC50 18.5 uM] | ||||
| yes [IC50 19.3 uM] | ||||
| yes [IC50 24.7 uM] | ||||
| yes [IC50 8.17 uM] | ||||
| yes [IC50 8.8 uM] |
Drug as victim
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| no | ||||
| no |
Tox targets
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
PubMed
| Title | Date | PubMed |
|---|---|---|
| AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases. | 2016-12-07 |
|
| Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non-small cell lung cancer. | 2016-03 |
|
| Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor. | 2015-10-22 |
Patents
Sample Use Guides
AZD-3759 is given at a dose of 50 mg, administered twice daily, or 160 mag, administered once daily.
Route of Administration:
Oral
100 uL of NCI-H3255 (EGFR L858R), NCI-H838 (EGFR wild type) and PC-9 (Exon 19 deletion EGFR) cells were seeded in 96 well cell culture plates and incubated at 37C with 5% CO2
overnight and then treated with AZD-3759 at concentrations ranging from 10 to 0.0003 mM. IC50s for cellular inhibition of EGFR phosphorylation were 7.2, 64.5, 7.7 nM, respectively. In cellular proliferation assay, the cells were exposed to concentrations of compounds ranging from 30 to 0.0003 mM for 72 hours. GI50 values were 7, 21556 and 7.7 nM, respectively.
| Substance Class |
Chemical
Created
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Edited
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05Z3WK3SO6
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