Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives as novel selective Axl inhibitors

被引：7

作者：

Inoue, Satoshi ^{[1
]}

Yamane, Yoshinobu ^{[1
]}

Tsukamoto, Shuntaro ^{[2
]}

Murai, Norio ^{[1
]}

Azuma, Hiroshi ^{[1
]}

Nagao, Satoshi ^{[1
]}

Nishibata, Kyoko ^{[2
]}

Fukushima, Sayo ^{[2
]}

Ichikawa, Kenji ^{[2
]}

Nakagawa, Takayuki ^{[2
]}

Sugi, Naoko Hata ^{[2
]}

Ito, Daisuke ^{[2
]}

Kato, Yu ^{[2
]}

Goto, Aya ^{[3
]}

Kakiuchi, Dai ^{[3
]}

Ueno, Takashi ^{[4
]}

Matsui, Junji ^{[2
]}

Matsushima, Tomohiro ^{[1
]}

机构：

[1] Eisai & Co Ltd, Tsukuba Res Labs, Med Chem, 5-1-3 Tokodai, Tsukuba, Ibaraki 3002635, Japan

[2] Eisai & Co Ltd, Tsukuba Res Labs, Biopharmacol, 5-1-3 Tokodai, Tsukuba, Ibaraki 3002635, Japan

[3] Eisai & Co Ltd, Tsukuba Res Labs, Drug Safety, 5-1-3 Tokodai, Tsukuba, Ibaraki 3002635, Japan

[4] Eisai & Co Ltd, Tsukuba Res Labs, Drug Metab & Pharmacokinet, 5-1-3 Tokodai, Tsukuba, Ibaraki 3002635, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2021年 / 48卷

关键词：

Axl; Mer; Structure-activity relationships; Cancer; Inhibitor; Small molecule; CANCER-CELLS; RESISTANCE; OVEREXPRESSION; THERAPY;

D O I：

10.1016/j.bmcl.2021.128247

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页数：7

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