title: Special ergolines efficiently inhibit the chemokine receptor CXCR3 in blood.
abstract: The structure-activity relationship of highly potent special ergolines which selectively block the chemokine receptor CXCR3 is reported. The most potent compounds showed IC(50) values below 10nM in both ligand binding and Ca(2+)-mobilization assays. However, these compounds were poorly active in an assay that measures receptor occupancy in blood. Introduction of polar substituents led to derivatives with IC(50) values below 10nM in this assay. Among them was compound 11a which showed both a favorable PK profile and cross reactivity with rodent CXCR3 making it a promising tool compound to further explore the role of CXCR3 in animal models.
authors.affiliation: Novartis Institutes for BioMedical Research, Forum 1, Novartis Campus, Lichtstrasse 35, CH-4056 Basel, Switzerland.
authors.forename: Gebhard
authors.initials: G
authors.lastname: Thoma
authors.forename: Rolf
authors.initials: R
authors.lastname: Baenteli
authors.forename: Ian
authors.initials: I
authors.lastname: Lewis
authors.forename: Darryl
authors.initials: D
authors.lastname: Jones
authors.forename: Jiri
authors.initials: J
authors.lastname: Kovarik
authors.forename: Markus B
authors.initials: MB
authors.lastname: Streiff
authors.forename: Hans-Guenter
authors.initials: HG
authors.lastname: Zerwes
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004873:Ergolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors* / Q000097:blood; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004873:Ergolines; D054367:Receptors, CXCR3