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.
Subject(s)
Central Nervous System/metabolism , ErbB Receptors/antagonists & inhibitors , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Quinazolines/pharmacology , Animals , Brain/diagnostic imaging , Brain/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/secondary , Clinical Trials, Phase I as Topic , Dogs , Drug Discovery , Macaca fascicularis , Male , Mice , Piperazines/chemical synthesis , Piperazines/therapeutic use , Positron-Emission Tomography , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/therapeutic use , Quinazolines/chemical synthesis , Quinazolines/therapeutic use , Rats , Rats, Wistar , Xenograft Model Antitumor AssaysABSTRACT
A series of 6-hydrazinopurine 2'-methyl ribonucleosides was synthesized and tested for its inhibitory activity against the hepatitis C virus (HCV). The lack of antiviral activity of these nucleosides was associated with a poor affinity for adenosine kinase, which prompted us to synthesize several of their 5'-monophosphate prodrugs. Some of these prodrugs exhibited more than 1000-fold improvement in anti-HCV activity when compared to their parent nucleosides (EC(50) of 24 nM vs 92 microM for the parent).
