title: Substituted 7-amino-5-thio-thiazolo[4,5-d]pyrimidines as potent and selective antagonists of the fractalkine receptor (CX3CR1).
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.
authors.affiliation: CNSP iMed Science Södertälje, AstraZeneca Research and Development, Innovative Medicines, SE-15185 Södertälje, Sweden. daggstigen@gmail.com
authors.forename: Sofia
authors.initials: S
authors.lastname: Karlström
authors.forename: Gunnar
authors.initials: G
authors.lastname: Nordvall
authors.forename: Daniel
authors.initials: D
authors.lastname: Sohn
authors.forename: Andreas
authors.initials: A
authors.lastname: Hettman
authors.forename: Dominika
authors.initials: D
authors.lastname: Turek
authors.forename: Kristofer
authors.initials: K
authors.lastname: Åhlin
authors.forename: Annika
authors.initials: A
authors.lastname: Kers
authors.forename: Martina
authors.initials: M
authors.lastname: Claesson
authors.forename: Can
authors.initials: C
authors.lastname: Slivo
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Lo-Alfredsson
authors.forename: Carl
authors.initials: C
authors.lastname: Petersson
authors.forename: Galina
authors.initials: G
authors.lastname: Bessidskaia
authors.forename: Per H
authors.initials: PH
authors.lastname: Svensson
authors.forename: Tobias
authors.initials: T
authors.lastname: Rein
authors.forename: Eva
authors.initials: E
authors.lastname: Jerning
authors.forename: Åsa
authors.initials: Å
authors.lastname: Malmberg
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ahlgen
authors.forename: Colin
authors.initials: C
authors.lastname: Ray
authors.forename: Lauri
authors.initials: L
authors.lastname: Vares
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ivanov
authors.forename: Rolf
authors.initials: R
authors.lastname: Johansson
mesh_terms: D000605:Amino Alcohols / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D018938:Caco-2 Cells; D006801:Humans; D009103:Multiple Sclerosis / Q000188:drug therapy*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C000609791:AZD8797; D000605:Amino Alcohols; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D011743:Pyrimidines; D019707:Receptors, Chemokine; D013844:Thiazoles