Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A2A/A2B adenosine receptor antagonists

被引：10

作者：

Li, Zhi ^{[1
]}

Kou, Lijuan ^{[1
]}

Fu, Xinzhen ^{[1
]}

Xie, Zeping ^{[1
]}

Xu, Maolei ^{[1
]}

Guo, Lin ^{[1
]}

Lin, Tiantian ^{[2
]}

Gong, Shizhou ^{[2
]}

Zhang, Shumin ^{[1
]}

Liu, Ming ^{[1
]}

机构：

[1] Binzhou Med Univ, Sch Pharm, Yantai 264003, Peoples R China

[2] Luye Pharma Grp, Yantai, Peoples R China

来源：

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY | 2022年 / 37卷 / 01期

关键词：

Dual A(2A); A(2B) adenosine receptor antagonists; quinoline; methylbenzonitrile; T cell activation; pharmacokinetics; ADENINE;

D O I：

10.1080/14756366.2022.2077731

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of novel dual A(2A)/A(2B) AR antagonists based on the triazole-pyrimidine-methylbenzonitrile core were designed and synthesised. The A(2A) AR antagonist cAMP functional assay results were encouraging for most target compounds containing quinoline or its open-ring bioisosteres. In addition, compound 7i displayed better inhibitory activity on A(2B) AR (IC50 14.12 nM) and higher potency in IL-2 production than AB928. Moreover, molecular docking studies were carried out to explain the rationality of molecular design and the activity of compound 7i. Further studies on 7f and 7i revealed good liver microsomes stabilities and acceptable in vivo PK profiles. This study provides insight into the future development of dual A(2A)/A(2B) AR antagonists for cancer immunotherapy.

引用

页码：1514 / 1526

页数：13

共 41 条

[1] Immunity, inflammation and cancer: a leading role for adenosine [J].

Antonioli, Luca ;

Blandizzi, Corrado ;

Pacher, Pal ;

Hasko, Gyoergy .

NATURE REVIEWS CANCER, 2013, 13 (12) :842-857

[2]

Bamford SJ., 2009, Patent, Patent No. [WO2009156737, 2009156737]

[3] Novel positive allosteric modulators of A2B adenosine receptor acting as bone mineralisation promoters [J].

Barresi, Elisabetta ;

Giacomelli, Chiara ;

Marchetti, Laura ;

Baglini, Emma ;

Salerno, Silvia ;

Greco, Giovanni ;

Settimo, Federico ;

Martini, Claudia ;

Trincavelli, Maria Letizia ;

Taliani, Sabrina .

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2021, 36 (01) :286-294

[4]

Beatty J., 2019, U.S. Patent, Patent No. [US10399962, 10399962, 10,399,962B2]

[5] Adenosine Receptor 2A Blockade Increases the Efficacy of Anti-PD-1 through Enhanced Antitumor T-cell Responses [J].

Beavis, Paul A. ;

Milenkovski, Nicole ;

Henderson, Melissa A. ;

John, Liza B. ;

Allard, Bertrand ;

Loi, Sherene ;

Kershaw, Michael H. ;

Stagg, John ;

Darcy, Phillip K. .

CANCER IMMUNOLOGY RESEARCH, 2015, 3 (05) :506-517

[6] The aminopyridine-3,5-dicarbonitrile core for the design of new non-nucleoside-like agonists of the human adenosine A2B receptor [J].

Betti, Marco ;

Catarzi, Daniela ;

Varano, Flavia ;

Falsini, Matteo ;

Varani, Katia ;

Vincenzi, Fabrizio ;

Ben Diego, Dal ;

Lambertucci, Catia ;

Colotta, Vittoria .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2018, 150 :127-139

[7]

Bobowska A., 2019, Preparation of imidazo[1,2-a]pyrazines as adenosine A 2A receptor modulators for the treatment of various diseases, Patent No. [WO2019002606, 2019002606]

[8] ADENINE ISOSTERES WITH BRIDGEHEAD NITROGEN .1. 2 INDEPENDENT SYNTHESES OF THE [1,2,4]TRIAZOLO[1,5-A][1,3,5]TRIAZINE RING-SYSTEM LEADING TO A RANGE OF SUBSTITUENTS IN THE 2-POSITION, 5-POSITION AND 7-POSITION [J].

CAULKETT, PWR ;

JONES, G ;

MCPARTLIN, M ;

RENSHAW, ND ;

STEWART, SK ;

WRIGHT, B .

JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1995, (07) :801-808

[9] Therapeutic Potentials of A2B Adenosine Receptor Ligands: Current Status and Perspectives [J].

Chandrasekaran, Balakumar ;

Samarneh, Sara ;

Jaber, Abdul Muttaleb Yousef ;

Kassab, Ghadir ;

Agrawal, Nikhil .

CURRENT PHARMACEUTICAL DESIGN, 2019, 25 (25) :2741-2771

[10] Trifluoromethyl-substituted 3,5-bis(arylidene)-4-piperidones as potential anti-hepatoma and anti-inflammation agents by inhibiting NF-κB activation [J].

Cong, Wei ;

Sun, Yue ;

Sun, Yi-Fan ;

Yan, Wei-Bin ;

Zhang, Yu-Long ;

Gao, Zhong-Fei ;

Wang, Chun-Hua ;

Hou, Gui-Ge ;

Zhang, Jia-Jing .

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2021, 36 (01) :1622-1631

← 1 2 3 4 5 →