Identification and structure-activity relationships of 1-aryl-3-piperidin-4-yl-urea derivatives as CXCR3 receptor antagonists

Daniel R Allen; Amanda Bolt; Gayle A Chapman; Roland L Knight; Johannes W G Meissner; David A Owen; Robert J Watson

doi:10.1016/j.bmcl.2006.10.088

Identification and structure-activity relationships of 1-aryl-3-piperidin-4-yl-urea derivatives as CXCR3 receptor antagonists

Bioorg Med Chem Lett. 2007 Feb 1;17(3):697-701. doi: 10.1016/j.bmcl.2006.10.088. Epub 2006 Nov 2.

Authors

Daniel R Allen¹, Amanda Bolt, Gayle A Chapman, Roland L Knight, Johannes W G Meissner, David A Owen, Robert J Watson

Affiliation

¹ UCB, Inflammation Discovery, Granta Park, Great Abington, Cambridge CB21 6GS, UK.

PMID: 17097877
DOI: 10.1016/j.bmcl.2006.10.088

Abstract

The synthesis and biological evaluation of a series of 1-aryl-3-piperidin-4-yl-urea derivatives as small-molecule CXCR3 antagonists is described. SAR studies resulted in significant improvement of potency and physicochemical properties and established the key pharmacophore of the series, and led to the identification of 9t, which exhibits an IC50 of 16 nM in the GTPgammaS35 functional assay.

MeSH terms

Animals
CHO Cells
Chemical Phenomena
Chemistry, Physical
Chemotaxis / drug effects
Cricetinae
Cricetulus
Guanosine 5'-O-(3-Thiotriphosphate) / pharmacology
In Vitro Techniques
Kinetics
Mice
Microsomes, Liver / drug effects
Microsomes, Liver / enzymology
Microsomes, Liver / metabolism
Piperidines / chemical synthesis*
Piperidines / pharmacology*
Receptors, CXCR3
Receptors, Chemokine / antagonists & inhibitors*
Structure-Activity Relationship
Transfection
Urea / analogs & derivatives*
Urea / chemical synthesis*
Urea / pharmacology*

Substances

Cxcr3 protein, mouse
Piperidines
Receptors, CXCR3
Receptors, Chemokine
Guanosine 5'-O-(3-Thiotriphosphate)
Urea