ABSTRACT
We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration.
Subject(s)
Antineoplastic Agents/pharmacology , ErbB Receptors/antagonists & inhibitors , Indazoles/pharmacology , Neoplasms, Experimental/drug therapy , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Dogs , Epidermal Growth Factor/pharmacology , Ether-A-Go-Go Potassium Channels , Female , Hepatocytes/cytology , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Indazoles/chemical synthesis , Keratinocytes/cytology , Keratinocytes/drug effects , Keratinocytes/metabolism , Lapatinib , Male , Metabolic Clearance Rate , Mice , Mice, Nude , Mice, SCID , Microsomes/drug effects , Molecular Structure , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Rats , Rats, Wistar , Survival Rate , Xenograft Model Antitumor AssaysABSTRACT
The structure-activity relationship of a novel subseries of 4-anilinoquinazoline EGFR inhibitors substituted at the C-6 position with carbon-linked side chains has been investigated. This exploration has led to the discovery of novel aminomethyl carboxamides with good biological, pharmacokinetic and physical properties.
