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J Med Chem. 2015 Oct 22;58(20):8200-15. doi: 10.1021/acs.jmedchem.5b01073. Epub 2015 Oct 9.

Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor.

Author information

1
Innovation Center China, Asia & Emerging Markets iMed, AstraZeneca Innovative Medicines and Early Development , 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
2
AstraZeneca Translational Centre, Personal Healthcare and Biomarkers iMed, AstraZeneca R&D, Karolinska Institutet , Department of Clinical Neuroscience, R5:U1 Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
3
Karolinska Institutet , Department of Clinical Neuroscience, Centre for Psychiatry Research, R5:02 Karolinska University Hospital, SE-171 76 Stockholm, Sweden.

Abstract

Recent reports suggest that an increasing number of patients with lung cancer, especially those with activating mutations of the epidermal growth factor receptor (EGFR), also present with brain metastases and leptomeningeal metastases. These patients have poor prognosis as there are no approved drugs for these indications. Available agents have poor efficacy for these patients even at well above their standard dose. Herein, we report the discovery of (4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl (2R)-2,4-dimethylpiperazine-1-carboxylate 1m (AZD3759), an investigational drug currently in Phase 1 clinical trial, which has excellent central nervous system penetration and which induces profound regression of brain metastases in a mouse model.

PMID:
26313252
DOI:
10.1021/acs.jmedchem.5b01073
[Indexed for MEDLINE]

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