Capped diaminopropionamide-glycine dipeptides are inhibitors of CC chemokine receptor 2 (CCR2) |
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Authors: | Carter Percy H Brown Gregory D Friedrich Sarah R Cherney Robert J Tebben Andrew J Lo Yvonne C Yang Gengjie Jezak Heather Solomon Kimberly A Scherle Peggy A Decicco Carl P |
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Institution: | Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. percy.carter@bms.com |
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Abstract: | 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. |
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