Discovery of 3,5-bis(trifluoromethyl)benzyl l-arylglycinamide based potent CCR2 antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 14, 2006, Pages 3735-3739

  Yang, Lihu ^a   Zhou, Changyou ^a   Guo, Liangqin ^a   Morriello, Gregori ^a   Butora, Gabor ^a   Pasternak, Alexander ^a   Parsons, William H ^a   Mills, Sander G ^a   MacCoss, Malcolm ^a   Vicario, Pasquale P ^a   Zweerink, Hans ^a   Ayala, Julia M ^a   Goyal, Shefali ^a   Hanlon, William A ^a   Cascieri, Margaret A ^a   Springer, Marty S ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Antagonist; CCL2; CCR2; CCR2b; Chemokine; Chemotaxis; GPCR; MCP 1

Indexed keywords

CALCIUM; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CCR2; CHEMOKINE RECEPTOR CCR2 ANTAGONIST; MONOCYTE CHEMOTACTIC PROTEIN 1; N [3,5 BIS(TRIFLUOROMETHYL)BENZYL] 2 [[2 (1 PIPERIDINYL)ETHYL]AMINO] 2 (3 THIENYL)ACETAMIDE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; CHEMOTAXIS; CHO CELL; CONTROLLED STUDY; DRUG ABSORPTION; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG POTENCY; DRUG SCREENING; HUMAN; HUMAN CELL; IC 50; MONOCYTE; NONHUMAN; RAT;

ANIMALS; BINDING SITES; CALCIUM; CHEMOKINE CCL2; CHO CELLS; CRICETINAE; GLYCINE; HUMANS; INHIBITORY CONCENTRATION 50; MODELS, BIOLOGICAL; MONOCYTES; RECEPTORS, CHEMOKINE;

EID: 33746547860     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.04.045     Document Type: Article

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30. 2, pH 7.4. 125I-hMCP-1 was purchased from Perkin Elmer Life Sciences, Inc., with a specific activity of 2200 Ci/mmol. The assay was terminated by filtration of the reaction mixture through GF/B filter plates (presoaked in 0.1% polyethyleneimine) using a Packard Cell Harvester. The filter plates were washed with 25 mM HEPES, pH 7.5, containing 500 mM NaCl and dried in an incubator at 37 °C for 30 min. The plates were loaded with Microscint 0 (Packard) and counted in a Topcount NXT (Packard). The software program Prism (GraphPad) was used for all calculations. All data represent mean values for at least two separate experiments.
31. 4) were incubated in cell culture medium containing Fluo-3, AM fluorescent dye (5 μg/mL, Molecular Probes), and probenicid (710 μg/mL, Sigma) for 1 h at 37 °C. Cells were washed with Hanks' buffer containing HEPES (20 mM), BSA (0.1%), and probenicid, and then were resuspended in 90 μL of the same buffer. A ligand addition plate was prepared by adding 135 μL of chemokines at various concentrations for the titration. To test inhibition of calcium release by TAK-779, 2 μL of this antagonist at various concentrations was added to the cells upon resuspension and 20 nM hMCP-1 was used to activate CCR2B receptors. Both plates were placed into the Fluorescence Imaging Plate Reader (FLIPR, Coherent, Inc.). Chemokines were dispensed from addition plate into the cell plate and calcium release was measured by the Argon Laser at an excitation wavelength of 488 nm and an emission wavelength of 530 nm.
32. 5 cells/well.