期刊
CURRENT MEDICINAL CHEMISTRY
卷 11, 期 6, 页码 709-719出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/0929867043455729
关键词
angiogenesis; vascular endothelial growth factor (VEGF); KDR kinase inhibitors; property-based design; solubility; cellular activity; pharmacokinetics; oral bioavailability
Small molecule inhibitors of KDR kinase activity have typically possessed poor intrinsic physical properties including low aqueous solubility and high lipophilicity. These features have often conferred limited cell permeability manifested in low levels of cell-based KDR inhibitory activity and oral bioavailability. Thus, the design of inhibitors with appropriate physical properties has played a critical role in the development of clinical candidates. We present a variety of structural modifications that have afforded improvements in physical properties and thereby have addressed suboptimal cellular potency and pharmacokinetics for three unique classes of KDR kinase inhibitors.
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