INCB3344 (INCB-3344 ) is a novel, potent, selective, orally bioavailable small molecule antagonist of the CCR2 receptor with anti-inflammatory activity. It inhibits CCR with IC50 values of 3.8 nM (hCCR2) and 7.8 nM (mCCR2) in antagonism of chemotaxis activity and 5.1 nM (hCCR2) and 9.5 nM (mCCR2) in binding antagonistic activity. Pharmacological studies of CCR2 antagonists and their potential therapeutic utility have been hindered by the inherent lack of rodent cross-reactivity in small molecule antagonists found to date. With nanomolar potency (IC(50) = 10 nM), INCB3344 inhibits CCL2 binding to mouse monocytes in vitro. It also exhibits dose-dependent inhibition of CCL2-mediated functional responses, including ERK phosphorylation and chemotaxis, with a similar potency. INCB3344 is at least 100-fold more selective for CCR2 than other G protein-coupled receptors against which other CC chemokine receptors are present. Because of its high oral bioavailability and systemic exposure in rodents, INCB3344 is suitable for in vivo pharmacological research. INCB3344 treatment results in a dose-dependent inhibition of macrophage influx in a mouse model of delayed-type hypersensitivity. The histopathological examination of tissues from the delayed-type hypersensitivity model indicates that CCR2 inhibition significantly reduces tissue inflammation, pointing to a potential orchestration role for macrophages in immune-based inflammatory responses. The investigation of INCB3344 in inflammatory disease models was prompted by these findings. In mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis, and in rats with inflammatory arthritis, therapeutic dosage of INCB3344 dramatically ameliorates disease. In conclusion, these findings lend support to the idea of treating chronic inflammatory diseases by targeting this receptor.

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