2. Academic Validation
  3. Discovery of disubstituted cyclohexanes as a new class of CC chemokine receptor 2 antagonists

Discovery of disubstituted cyclohexanes as a new class of CC chemokine receptor 2 antagonists

  • J Med Chem. 2008 Feb 28;51(4):721-4. doi: 10.1021/jm701488f.
Robert J Cherney,  Ruowei Mo,  Dayton T Meyer,  David J Nelson,  Yvonne C Lo,  Gengjie Yang,  Peggy A Scherle,  Sandhya Mandlekar,  Zelda R Wasserman,  Heather Jezak,  Kimberly A Solomon,  Andrew J Tebben,  Percy H Carter,  Carl P Decicco
PMID: 18232650 DOI: 10.1021/jm701488f
Abstract

We describe the design, synthesis, and evaluation of novel disubstituted cyclohexanes as potent CCR2 antagonists. Exploratory SAR studies led to the cis-disubstituted derivative 22, which displayed excellent binding affinity for CCR2 (binding IC50 = 5.1 nM) and potent functional antagonism (calcium flux IC50 = 18 nM and chemotaxis IC 50 = 1 nM). Site-directed mutagenesis studies with 22 suggest the compound is binding near the key receptor residue Glu291, however, 22 is not reliant on Glu291 for its binding affinity.

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