Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A2A/A2B adenosine receptor antagonists
A series of novel dual A2A/A2B AR antagonists based on the triazole-pyrimidine-methylbenzonitrile core were designed and synthesised. The A2A AR antagonist cAMP functional assay results were encouraging for most target compounds containing quinoline or its open-ring bioisosteres. In addition, compou...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2022-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2022.2077731 |
| _version_ | 1811335647041945600 |
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| author | Zhi Li Lijuan Kou Xinzhen Fu Zeping Xie Maolei Xu Lin Guo Tiantian Lin Shizhou Gong Shumin Zhang Ming Liu |
| author_facet | Zhi Li Lijuan Kou Xinzhen Fu Zeping Xie Maolei Xu Lin Guo Tiantian Lin Shizhou Gong Shumin Zhang Ming Liu |
| author_sort | Zhi Li |
| collection | DOAJ |
| description | A series of novel dual A2A/A2B AR antagonists based on the triazole-pyrimidine-methylbenzonitrile core were designed and synthesised. The A2A 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 A2B 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 A2A/A2B AR antagonists for cancer immunotherapy. |
| first_indexed | 2024-04-13T17:28:13Z |
| format | Article |
| id | doaj.art-dae3bf8349fc4ffbbbb6c97e675391dc |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-04-13T17:28:13Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-dae3bf8349fc4ffbbbb6c97e675391dc2022-12-22T02:37:42ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742022-12-013711514152610.1080/14756366.2022.2077731Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A2A/A2B adenosine receptor antagonistsZhi Li0Lijuan Kou1Xinzhen Fu2Zeping Xie3Maolei Xu4Lin Guo5Tiantian Lin6Shizhou Gong7Shumin Zhang8Ming Liu9School of Pharmacy, Binzhou Medical University, Yantai, ChinaSchool of Pharmacy, Binzhou Medical University, Yantai, ChinaSchool of Pharmacy, Binzhou Medical University, Yantai, ChinaSchool of Pharmacy, Binzhou Medical University, Yantai, ChinaSchool of Pharmacy, Binzhou Medical University, Yantai, ChinaSchool of Pharmacy, Binzhou Medical University, Yantai, ChinaLuye Pharma Group, Yantai, ChinaLuye Pharma Group, Yantai, ChinaSchool of Pharmacy, Binzhou Medical University, Yantai, ChinaSchool of Pharmacy, Binzhou Medical University, Yantai, ChinaA series of novel dual A2A/A2B AR antagonists based on the triazole-pyrimidine-methylbenzonitrile core were designed and synthesised. The A2A 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 A2B 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 A2A/A2B AR antagonists for cancer immunotherapy.https://www.tandfonline.com/doi/10.1080/14756366.2022.2077731Dual A2A/A2B adenosine receptor antagonistsquinolinemethylbenzonitrileT cell activationpharmacokinetics |
| spellingShingle | Zhi Li Lijuan Kou Xinzhen Fu Zeping Xie Maolei Xu Lin Guo Tiantian Lin Shizhou Gong Shumin Zhang Ming Liu Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A2A/A2B adenosine receptor antagonists Journal of Enzyme Inhibition and Medicinal Chemistry Dual A2A/A2B adenosine receptor antagonists quinoline methylbenzonitrile T cell activation pharmacokinetics |
| title | Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A2A/A2B adenosine receptor antagonists |
| title_full | Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A2A/A2B adenosine receptor antagonists |
| title_fullStr | Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A2A/A2B adenosine receptor antagonists |
| title_full_unstemmed | Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A2A/A2B adenosine receptor antagonists |
| title_short | Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A2A/A2B adenosine receptor antagonists |
| title_sort | design synthesis and biological evaluation of triazole pyrimidine methylbenzonitrile derivatives as dual a2a a2b adenosine receptor antagonists |
| topic | Dual A2A/A2B adenosine receptor antagonists quinoline methylbenzonitrile T cell activation pharmacokinetics |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2022.2077731 |
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