title: CXCR3 antagonists: quaternary ammonium salts equipped with biphenyl- and polycycloaliphatic-anchors.
abstract: Small-molecule ligands for the CXCR3 chemokine receptor receive considerable attention as a means to interrogate the roles of CXCR3 in vitro and in vivo and/or to potentially treat various conditions such as inflammatory diseases and cancer. We have synthesized and explored a novel class of small-molecule antagonists for CXCR3. A medium-throughput screen revealed an adamantane-guanidine as a hit. The guanidine unit was replaced by a small quaternary ammonium group, leading to ca. 5-fold increase in affinity. Substitution of the adamantane group by a myrtenyl moiety further increased affinity, while the benzyl group was decorated with an additional (substituted) aryl ring. This led to the identification of several bisaryl-based ligands with CXCR3 affinities of around 100 nM and with the ability to antagonize the functional activity of CXCL10.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Maikel
authors.initials: M
authors.lastname: Wijtmans
authors.forename: Dennis
authors.initials: D
authors.lastname: Verzijl
authors.forename: Serge
authors.initials: S
authors.lastname: Bergmans
authors.forename: Michael
authors.initials: M
authors.lastname: Lai
authors.forename: Leontien
authors.initials: L
authors.lastname: Bosch
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D001713:Biphenyl Compounds / Q000737:chemistry*; D002460:Cell Line; D019791:Guanidine / Q000737:chemistry; D006801:Humans; D011083:Polycyclic Compounds / Q000737:chemistry*; D011485:Protein Binding; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012492:Salts / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D001713:Biphenyl Compounds; D019791:Guanidine; D011083:Polycyclic Compounds; D000644:Quaternary Ammonium Compounds; D054367:Receptors, CXCR3; D012492:Salts; C010574:biphenyl