Special ergolines efficiently inhibit the chemokine receptor CXCR3 in blood

The structure–activity relationship of highly potent special ergolines which selectively block the chemokine receptor CXCR3 is reported. The most potent compounds showed IC50 values below 10nM in both ligand binding and Ca2+-mobilization assays. However, these compounds were poorly active in an assa...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-08, Vol.21 (16), p.4745-4749
Hauptverfasser:	Thoma, Gebhard, Baenteli, Rolf, Lewis, Ian, Jones, Darryl, Kovarik, Jiri, Streiff, Markus B., Zerwes, Hans-Guenter
Format:	Artikel
Sprache:	eng
Schlagworte:	animal models Animals Biological and medical sciences blood chemokines CXCL10 CXCL11 CXCL9 CXCR3 Dose-Response Relationship, Drug Ergoline Ergolines - chemical synthesis Ergolines - chemistry Ergolines - pharmacology Humans inhibitory concentration 50 Medical sciences Molecular Structure Pharmacology. Drug treatments Rats receptors Receptors, CXCR3 - antagonists & inhibitors Receptors, CXCR3 - blood rodents Stereoisomerism Structure-Activity Relationship structure-activity relationships
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Zusammenfassung:	The structure–activity relationship of highly potent special ergolines which selectively block the chemokine receptor CXCR3 is reported. The most potent compounds showed IC50 values below 10nM in both ligand binding and Ca2+-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 IC50 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.06.070