[摘要]：Previous studies with perzinfotel, 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 perzinfotel (3-5%), prodrug derivs. were synthesized and evaluated. The oxymethylene-spaced di-Ph analog (I) demonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, I was rapidly converted to perzinfotel. Pharmacokinetic studies indicated that the amt. of systemic exposure of perzinfotel produced by a 10 mg/kg oral dose of I was 2.5-fold greater than that produced by a 30 mg/kg oral dose of perzinfotel. Consistent with these results, I was significantly more potent and had a longer duration of activity than perzinfotel following oral administration in a rodent model of inflammatory pain. Taken together, these results demonstrate that an oxymethylene-spaced prodrug approach increased the bioavailability of perzinfotel.
