Prodrugs of Perzinfotel with Improved Oral Bioavailability
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- 作者：Reinhardt B. Baudy ; John A. Butera ; Magid A. Abou-Gharbia ; Hong Chen ; Boyd Harrison ; Uday Jain ; Ronald Magolda ; Jean Y. Sze ; Michael R. Brandt ; Terri A. Cummons ; Diane Kowal ; Menelas N. Pangalos ; Boja
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：February 12, 2009
- 年：2009
- 卷：52
- 期：3
- 页码：771-778
- 全文大小：219K
- 年卷期：v.52,no.3(February 12, 2009)
- ISSN：1520-4804
文摘
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 3a demonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, 3a was rapidly converted to 1 via 2a. Pharmacokinetic studies indicated that the amount of systemic exposure of 1 produced by a 10 mg/kg oral dose of 3a was 2.5-fold greater than that produced by a 30 mg/kg oral dose of 1. Consistent with these results, 3a was significantly more potent and had a longer duration of activity than 1 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 1.