PMID- 19576173
OWN - NLM
STAT- MEDLINE
DCOM- 20090820
LR  - 20091119
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 387
IP  - 2
DP  - 2009 Sep 18
TI  - Pharmacological characterization of INCB3344, a small molecule antagonist of 
      human CCR2.
PG  - 251-5
LID - 10.1016/j.bbrc.2009.06.135 [doi]
AB  - The chemokine receptor 2 (CCR2) directs migration of monocytes and has been 
      proposed to be a drug target for chronic inflammatory diseases. INCB3344 was 
      first published as a small molecule nanomolar inhibitor of rodent CCR2. Here, we 
      show that INCB3344 can also bind human CCR2 (hCCR2) with high affinity, having a 
      dissociation constant (K(d)) of approximately 5nM. The binding of the compound to 
      the receptor is rapid and reversible. INCB3344 potently inhibits hCCR2 binding of 
      monocyte chemoattractant protein-1 (MCP-1) and MCP-1-induced signaling and 
      function in hCCR2-expressing cells, including ERK phosphorylation and chemotaxis, 
      and is competitive against MCP-1 in vitro. INCB3344 also blocks MCP-1 binding to 
      monocytes in human whole blood, with potency consistent with in vitro studies. 
      The whole blood binding assay described here can be used for monitoring 
      pharmacodynamic activity of CCR2 antagonists in both preclinical models and in 
      the clinic.
FAU - Shin, Niu
AU  - Shin N
AD  - Department of In Vitro Biology, Incyte Corporation, Wilmington, DE, United 
      States.
FAU - Baribaud, Frederic
AU  - Baribaud F
FAU - Wang, Kathy
AU  - Wang K
FAU - Yang, Genjie
AU  - Yang G
FAU - Wynn, Rich
AU  - Wynn R
FAU - Covington, Maryanne B
AU  - Covington MB
FAU - Feldman, Patricia
AU  - Feldman P
FAU - Gallagher, Karen B
AU  - Gallagher KB
FAU - Leffet, Lynn M
AU  - Leffet LM
FAU - Lo, Yvonne Y
AU  - Lo YY
FAU - Wang, Anlai
AU  - Wang A
FAU - Xue, Chu-Biao
AU  - Xue CB
FAU - Newton, Robert C
AU  - Newton RC
FAU - Scherle, Peggy A
AU  - Scherle PA
LA  - eng
PT  - Journal Article
DEP - 20090701
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (CCR2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (INCB3344)
RN  - 0 (Pyrrolidines)
RN  - 0 (Receptors, CCR2)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Biological Assay
MH  - Cells, Cultured
MH  - Chemokine CCL2/metabolism
MH  - Chemotaxis
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Flow Cytometry/methods
MH  - Humans
MH  - Leukocytes, Mononuclear/drug effects/metabolism
MH  - Phosphorylation
MH  - Pyrrolidines/metabolism/*pharmacology
MH  - Receptors, CCR2/*antagonists & inhibitors
EDAT- 2009/07/07 09:00
MHDA- 2009/08/21 09:00
CRDT- 2009/07/07 09:00
PHST- 2009/06/25 00:00 [received]
PHST- 2009/06/29 00:00 [accepted]
PHST- 2009/07/07 09:00 [entrez]
PHST- 2009/07/07 09:00 [pubmed]
PHST- 2009/08/21 09:00 [medline]
AID - S0006-291X(09)01302-3 [pii]
AID - 10.1016/j.bbrc.2009.06.135 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2009 Sep 18;387(2):251-5. doi: 
      10.1016/j.bbrc.2009.06.135. Epub 2009 Jul 1.