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Previous studies with perzinfotel (1), a potent, selective, competitive NMDA receptor antagonist, showed it to be efficacious in inflammatory and neuropathic pain models. To increase the low oral bioavailability of 1(3−5%), prodrug derivatives (3a−h) were synthesized and evaluated. The oxymethylene-spaced diphenyl analogue 3ademonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, 3awas rapidly converted to 1via 2a. Pharmacokinetic studies indicated that the amount of systemic exposure of 1produced by a 10 mg/kg oral dose of 3awas 2.5-fold greater than that produced by a 30 mg/kg oral dose of 1. Consistent with these results, 3awas significantly more potent and had a longer duration of activity than 1following oral administration in a rodent model of inflammatory pain. Taken together, these results demonstrate that an oxymethylene-spaced prodrug approach increased the bioavailability of 1. [ABSTRACT FROM AUTHOR]