INCB3344

Description

INCB 3344 is an antagonist of chemokine (C-C motif) receptor 2 (CCR2; IC₅₀ = 10 nM in WEHI-274 murine monocytes). It is selective for CCR2 over a panel of G protein-coupled receptors, including CCR1 and CCR5, with IC₅₀s values greater than 1 μM. INCB 3344 inhibits chemotaxis of WEHI-274 cells induced by chemokine (C-C motif) ligand 2 (CCL2; IC₅₀ = 10 nM) and CCL2-induced phosphorylation of ERK in WEHI-274 cells. It inhibits monocyte influx in a mouse model of peritonitis induced by thioglycolate when administered at doses of 60 and 100 mg/kg. INCB 3344 (30, 50, and 100 mg/kg twice per day) decreases the expression of CCR2 mRNA in the ear and reduces ear swelling in a mouse model of delayed-type hypersensitivity reaction. It prevents increases in or reduces macrophage levels in the spinal cord when administered at a dose of 100 mg/kg per day beginning the day of immunization or seven days following immunization, respectively, in a mouse model of experimental autoimmune encephalomyelitis (EAE). It also reduces disease incidence and severity in the same model and reduces disease severity in a rat model of adjuvant-induced arthritis. INCB 3344 reduces macrophage infiltration to the kidney and improves renal function in a mouse model of polycystic kidney disease.

Uses

INCB3344 is a potent, selective and orally bioavailable CCR2 antagonist with IC50 values of 5.1 nM (hCCR2) and 9.5 nM (mCCR2) in binding antagonism and 3.8 nM (hCCR2) and 7.8 nM (mCCR2) in antagonism of chemotaxis activity.

in vivo

IC 50

hCCR2: 5.1 nM (IC₅₀); mCCR2: 9.5 nM (IC₅₀)

References

[1]. brodmerkel c m, huber r, covington m, et al. discovery and pharmacological characterization of a novel rodent-active ccr2 antagonist, incb3344[j]. the journal of immunology, 2005, 175(8): 5370-5378.