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

共 50 条

[31] Synthesis and Cytotoxicity of Novel Diaryl Ureas Containing 2-Amino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl Group
Yao Peng
Xue Hao
Liu Qian
Liu Hong-tao
Chen Ming-jia
Gong Ping
CHEMICAL RESEARCH IN CHINESE UNIVERSITIES, 2010, 26 (04) : 558 - 562
[32] Identification of Pyrido[3,4-d]pyrimidine derivatives as RIPK3-Mediated necroptosis inhibitors
Kim, Namkyoung
Park, Chan-Jung
Kim, Younghoon
Ryu, SeongShick
Cho, Hanna
Nam, Yunju
Han, Myeonggil
Shin, Jeon-Soo
Sim, Taebo
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2023, 259
[33] Pyrazolo[3,4-d]pyrimidine derivatives as irreversible Bruton's tyrosine kinase inhibitors
Yeom, Hyesu
Achary, Raghavendra
Choi, Yunha
Park, Chi Hoon
Lee, Joo-Youn
Lee, Heung Kyoung
Kim, Pilho
Cho, Sung Yun
BULLETIN OF THE KOREAN CHEMICAL SOCIETY, 2022, 43 (04) : 577 - 584
[34] Design, synthesis and antitumor activity of novel pyrazolo[3,4-d]pyrimidine derivatives as EGFR-TK inhibitors
Abdelgawad, Mohamed A.
Bakr, Rania B.
Alkhoja, Olla A.
Mohamed, Wafaa R.
BIOORGANIC CHEMISTRY, 2016, 66 : 88 - 96
[35] 5,6,7,8-Tetrahydropyrido[4,3-c]pyridazine: A Lead-Oriented Scaffold with Two Diversity Points
Borisov, Alexander V.
Voloshchuk, Volodymyr V.
Nechayev, Maxim A.
Grygorenko, Oleksandr O.
SYNTHESIS-STUTTGART, 2013, 45 (17): : 2413 - 2416
[36] Synthesis and Cytotoxicity of Novel Diaryl Ureas Containing 2-Amino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl Group
YAO Peng
Chemical Research in Chinese Universities, 2010, 26 (04) : 558 - 562
[37] NEW SYNTHESES OF PYRAZOLO[3,4-D]PYRIMIDINE, PYRAZOLO[3,4-D]PYRIDAZINE, ISOINDOLINEDIONE AND PYRAZOLE DERIVATIVES
ABDELHAMID, AO
NEGM, AM
ABBAS, IM
JOURNAL FUR PRAKTISCHE CHEMIE, 1989, 331 (01): : 31 - 36
[38] A FACILE PREPARATION OF 7-(SUBSTITUTED AMINO)-6H-PYRROLO[3,4-D]-PYRIMIDINE DERIVATIVES
NOGUCHI, M
KIRIKI, Y
KAJIGAESHI, S
BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, 1989, 62 (09) : 3043 - 3045
[39] STUDIES ON PYRAZOLO[3,4-D]PYRIMIDINE DERIVATIVES .4. ON 1-METHYL-1H-PYRAZOLO[3,4-D]PYRIMIDINE AND 1-PHENYL-1H-PYRAZOLO[3,4-D]PYRIMIDINE 5-OXIDE
HIGASHINO, T
IWAI, Y
HAYASHI, E
CHEMICAL & PHARMACEUTICAL BULLETIN, 1976, 24 (12) : 3120 - 3134
[40] COMPOUNDS IN PYRROLO[3,4-D]PYRIMIDINE SERIES . DERIVATIVES WITH 6-ARYL SUBSTITUENTS
SOUTHWICK, PL
MADHAV, R
FITZGERA.JA
JOURNAL OF HETEROCYCLIC CHEMISTRY, 1969, 6 (04) : 507 - +

← 1 2 3 4 5 →