基于 4,6-二取代-2-巯基吡啶支架的第三代 CD73 抑制剂。

IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2024-12-13 DOI:10.1002/cmdc.202400662
Félix Grosjean, Maria Shaldaeva, Emeline Cros-Perrial, Céline Rodriguez, Rayane Ghoteimi, Aurélien Lebrun, Zhan-Guo Gao, Jean-Pierre Uttaro, Christophe Mathé, Kenneth Jacobson, Lars Petter Jordheim, Christine Ménétrier-Caux, Laurent Chaloin, Suzanne Peyrottes
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引用次数: 0

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本文章由计算机程序翻译,如有差异,请以英文原文为准。
Third-Generation CD73 Inhibitors Based on a 4,6-Disubstituted-2-thiopyridine Scaffold.

Various series of 4,6-disubstituted-2-thiopyridine derivatives were synthesized and evaluated as potential ecto-5'-nucleotidase (CD73) inhibitors. Altogether, about ninety compounds were prepared using a general synthetic pathway involving one or two steps (eventually one-pot) procedures. Variation of the nature of the substituents in positions 4 and 6 (methyl, trifluoromethyl or phenyl) of the thiopurine ring, as well as on the thiol function, was examined and led to marked differences both in term of reactivity and ability to interfere with the putative target protein. Using a functional assay on immune cells, few compounds belonging to series 4 were shown to be able to antagonize the inhibition of the T-cell proliferation at both 100µM and 10µM (completely for 4ab and partially for 4ai), that is as potent as AOPCP which entirely reversed the inhibitory impact of exogenous ATP on T cell proliferation until 62.5 µM. In addition, we have shown that both compounds (4ab and 4ai) were also capable of moderately inhibiting the hA2A receptor with Ki in the µmolar range in HEK-293 cells. Thus, with the aim to reduce the molecular size and the lipophilicity of our initial scaffold, we finally observed by serendipity a modification of the potential target of our compounds.

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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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