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

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• 作者：Sofia Karlstr枚m ; Gunnar Nordvall ; Daniel Sohn ; Andreas Hettman ; Dominika Turek ; Kristofer 脜hlin ; Annika Kers ; Martina Claesson ; Can Slivo ; Yvonne Lo-Alfredsson ; Carl Petersson ; Galina Bessidskaia ; Per H. Svensson ; Tobias Rein ; Eva Jerning ; 脜sa Malmberg ; Charlotte Ahlgen ; Colin Ray ; Lauri Vares ; Vladimir Ivanov ; Rolf Johansson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 25, 2013
• 年：2013
• 卷：56
• 期：8
• 页码：3177-3190
• 全文大小：513K
• 年卷期：v.56,no.8(April 25, 2013)
• ISSN：1520-4804

文摘

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鈥揳ctivity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with 伪-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.