2. Academic Validation
  3. Substituted 7-amino-5-thio-thiazolo[4,5-d]pyrimidines as potent and selective antagonists of the fractalkine receptor (CX3CR1)

Substituted 7-amino-5-thio-thiazolo[4,5-d]pyrimidines as potent and selective antagonists of the fractalkine receptor (CX3CR1)

  • J Med Chem. 2013 Apr 25;56(8):3177-90. doi: 10.1021/jm3012273.
Sofia Karlström 1,  Gunnar Nordvall,  Daniel Sohn,  Andreas Hettman,  Dominika Turek,  Kristofer Åhlin,  Annika Kers,  Martina Claesson,  Can Slivo,  Yvonne Lo-Alfredsson,  Carl Petersson,  Galina Bessidskaia,  Per H Svensson,  Tobias Rein,  Eva Jerning,  Åsa Malmberg,  Charlotte Ahlgen,  Colin Ray,  Lauri Vares,  Vladimir Ivanov,  Rolf Johansson
Affiliations

Affiliation

  • 1 CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-15185 Södertälje, Sweden. [email protected]
PMID: 23516963 DOI: 10.1021/jm3012273
Abstract

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-d]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 18a and 24h. We show the preparation of the first potent and selective orally available CX3CR1 antagonists.

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