Substituted 7‑Amino-5-thio-thiazolo[4,5‑<i>d</i>]pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX₃CR1)

We have developed two parallel series, A and B, of CX₃CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo­[4,5-<i>d</i>]­pyrimidine core structure, we were able to achieve compounds with high selectivity for CX₃CR1 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 CX₃CR1 antagonists