期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 48, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2021.128247
关键词
Axl; Mer; Structure-activity relationships; Cancer; Inhibitor; Small molecule
Novel 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives were designed and synthesized to evaluate their inhibitory activities on Axl and Mer, resulting in the identification of ER-001259851-000 as a potent and selective Axl inhibitor with drug-likeness and promising pharmacokinetic profile in mice.
Axl and Mer are members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases. Previously, we reported that enzyme-mediated inhibition of Mer by an Axl/Mer dual inhibitor led to retinal toxicity in mice, whereas selective Axl inhibition by compound 1 did not. On the other hand, compound 1 showed low membrane permeability. Here, we designed and synthesized a novel series of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives and evaluated their Axl and Mer inhibitory activities, leading to identification of ER-001259851-000 as a potent and selective Axl inhibitor with drug-likeness and a promising pharmacokinetic profile in mice.
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