Third-Generation CD73 Inhibitors Based on a 4,6-Disubstituted-2-thiopyridine Scaffold.

Abstract

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.