Description: AZD2423 (AZD-2423) is a novel and potent negative allosteric modulator of CCR2 with the potential to be used in posttraumatic neuralgia. AZD2423 inhibited CCR2 Ca2+ flux with an IC50 of 1.2 nM. AZD2423 is an orally bioavailable non-competitive, negative allosteric modulator of the CCR2 chemokine receptor. CCR2 is a receptor for monocyte chemoattractant protein MCP-1 (CCL2) and the closely related proteins MCP-2 (CCL8), MCP-3 (CCL7), and MCP-4 (CCL13). Human CCR2 exists as two forms, CCR2a and CCR2b, which differ at their C-termini by alternative splicing. Evidence obtained from studies on leukocytes suggests that MCP-1 binds preferentially to CCR2 and mediates monocyte chemotaxis. Studies have implicated MCP-1-mediated monocyte infiltration in pain and a range of inflammatory diseases. AZD2423 has been developed for the oral treatment of neuropathic pain and chronic obstructive pulmonary disease (COPD). In pre-clinical studies, AZD2423 inhibited MCP-1 induced calcium mobilization and chemotaxis of THP-1 cell line with an IC50 of 4 nM. The AZD2423 affinity for CCR2 in human whole blood, measuring MCP-1 induced L-selectin shedding from monocytes, was the same. AZD2423 is highly selective (> 500-fold) for CCR2. AZD2423 demonstrated robust analgesia in two rodent models of neuropathic pain and a pain model of joint destruction against heat, mechanical and weight-bearing endpoints. A significant (> 500-fold) drop-off in potency was observed for several pre-clinical species (rat, mouse, dog, marmoset). Consequently several tool compounds have been used for most in vivo pharmacology studies; a tool CCR2 antagonist inhibited neuronal excitability in rat neuropathic models to heat, mechanical and electrical stimuli either via systemic administration or via administration directly to the spinal cord.