Identification and initial evaluation of 4-N-aryl-[1,4]diazepane ureas as potent CXCR3 antagonists.
The identification and evaluation of aryl-[1,4]diazepane ureas as functional antagonists of the chemokine receptor CXCR3 are described. Specific examples exhibit IC(50) values of approximately 60 nM in a calcium mobilization functional assay, and dose-dependently inhibit CXCR3 functional response to CXCL11 (interferon-inducible T-cell alpha chemoattractant/I-TAC) as measured by T-cell chemotaxis, with a potency of approximately 100 nM.
Cole
Andrew G
AG
Pharmacopeia Drug Discovery, Inc., PO Box 5350, Princeton, NJ 08543, USA. acole@pcop.com
Stroke
Ilana L
IL
Brescia
Marc-Raleigh
MR
Simhadri
Srilatha
S
Zhang
Joan J
JJ
Hussain
Zahid
Z
Snider
Michael
M
Haskell
Christopher
C
Ribeiro
Sofia
S
Appell
Kenneth C
KC
Henderson
Ian
I
Webb
Maria L
ML
D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000737:chemistry; D002633:Chemotaxis; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004583:Electrons; D006801:Humans; D007249:Inflammation; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D013237:Stereoisomerism; D013601:T-Lymphocytes / Q000166:cytology; D014508:Urea / Q000737:chemistry*
C515202:CXCL11 protein, human; C515187:CXCR3 protein, human; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D014508:Urea; D002118:Calcium