1. Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives as novel selective Axl inhibitors
- Author
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Takayuki Nakagawa, Kyoko Nishibata, Takashi Ueno, Yu Kato, Yoshinobu Yamane, Norio Murai, Sayo Fukushima, Satoshi Inoue, Hiroshi Azuma, Aya Goto, Tomohiro Matsushima, Junji Matsui, Shuntaro Tsukamoto, Naoko Hata Sugi, Nagao Satoshi, Daisuke Ito, Kenji Ichikawa, and Dai Kakiuchi
- Subjects
Pyrimidine ,Membrane permeability ,Pyridines ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Receptor tyrosine kinase ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Proto-Oncogene Proteins ,Drug Discovery ,Animals ,Humans ,Molecular Biology ,Protein Kinase Inhibitors ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,c-Mer Tyrosine Kinase ,Organic Chemistry ,Dual inhibitor ,Receptor Protein-Tyrosine Kinases ,Molecular biology ,Small molecule ,Axl Receptor Tyrosine Kinase ,Retinal toxicity ,Pyrimidines ,chemistry ,biology.protein ,Microsomes, Liver ,Molecular Medicine - Abstract
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.
- Published
- 2021