Capped diaminopropionamide-glycine dipeptides are inhibitors of CC chemokine receptor 2 (CCR2).
A new series of CCR2 antagonists has been discovered that incorporates intramolecular hydrogen bonding as a strategy for rigidifying the scaffold. The structure-activity relationship was established through initial systematic modification of substitution pattern and chain length, followed by independent optimization of three different substituents (benzylamine, carboxamide, and benzamide). Several of the acyclic compounds display 10-30 nM binding affinity for CCR2. Moreover, these antagonists are able to block both MCP-1-induced Ca(2+) flux and monocyte chemotaxis, and are selective for binding to CCR2 over CCR1 and CCR3.
Carter
Percy H
PH
Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. percy.carter@bms.com
Brown
Gregory D
GD
Friedrich
Sarah R
SR
Cherney
Robert J
RJ
Tebben
Andrew J
AJ
Lo
Yvonne C
YC
Yang
Gengjie
G
Jezak
Heather
H
Solomon
Kimberly A
KA
Scherle
Peggy A
PA
Decicco
Carl P
CP
D002118:Calcium / Q000378:metabolism; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D008968:Molecular Conformation; D009000:Monocytes / Q000187:drug effects; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004151:Dipeptides; D007202:Indicators and Reagents; D054390:Receptors, CCR2; D002118:Calcium