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Substituted 7‑Amino-5-thio-thiazolo[4,5‑<i>d</i>]pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX<sub>3</sub>CR1)
We have developed two parallel series,
A and B, of CX<sub>3</sub>CR1 antagonists for the treatment of multiple
sclerosis. By modifying
the substituents on the 7-amino-5-thio-thiazoloÂ[4,5-<i>d</i>]Âpyrimidine core structure, we were able to achieve compounds with
high selectivity for CX<sub>3</sub>CR1 over the closely related CXCR2
receptor. The structure–activity relationships showed that
a leucinol moiety attached to the core-structure in the 7-position
together with α-methyl branched benzyl derivatives in the 5-position
displayed promising affinity, and selectivity as well as physicochemical
properties, as exemplified by compounds <b>18a</b> and <b>24h</b>. We show the preparation of the first potent and selective
orally available CX<sub>3</sub>CR1 antagonists