INCB3344

Description: INCB3344 is a novel, potent, selective, orally bioavailable small molecule antagonist of the CCR2 receptor 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. The lack of rodent cross-reactivity inherent in the small molecule CCR2 antagonists discovered to date has precluded pharmacological studies of antagonists of this receptor and its therapeutic relevance. In vitro, INCB3344 inhibits the binding of CCL2 to mouse monocytes with nanomolar potency (IC(50) = 10 nM) and displays dose-dependent inhibition of CCL2-mediated functional responses such as ERK phosphorylation and chemotaxis with similar potency. Against a panel of G protein-coupled receptors that includes other CC chemokine receptors, INCB3344 is at least 100-fold selective for CCR2. INCB3344 possesses good oral bioavailability and systemic exposure in rodents that allows in vivo pharmacological studies. INCB3344 treatment results in a dose-dependent inhibition of macrophage influx in a mouse model of delayed-type hypersensitivity. The histopathological analysis of tissues from the delayed-type hypersensitivity model demonstrates that inhibition of CCR2 leads to a substantial reduction in tissue inflammation, suggesting that macrophages play an orchestrating role in immune-based inflammatory reactions. These results led to the investigation of INCB3344 in inflammatory disease models. Therapeutic dosing of INCB3344 significantly reduces disease in mice subjected to experimental autoimmune encephalomyelitis, a model of multiple sclerosis, as well as a rat model of inflammatory arthritis. In summary, these data support targeting this receptor for the treatment of chronic inflammatory diseases.

References: J Immunol. 2005 Oct 15; 175(8):5370-8; Bioorg Med Chem Lett. 2010 Dec 15; 20(24):7473-8.

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