title: Prodrugs of perzinfotel with improved oral bioavailability.
abstract: 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.
authors.affiliation: Chemical & Screening Sciences, Wyeth Research, CN-8000, Princeton, New Jersey 08543, USA.
authors.forename: Reinhardt B
authors.initials: RB
authors.lastname: Baudy
authors.forename: John A
authors.initials: JA
authors.lastname: Butera
authors.forename: Magid A
authors.initials: MA
authors.lastname: Abou-Gharbia
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Boyd
authors.initials: B
authors.lastname: Harrison
authors.forename: Uday
authors.initials: U
authors.lastname: Jain
authors.forename: Ronald
authors.initials: R
authors.lastname: Magolda
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Sze
authors.forename: Michael R
authors.initials: MR
authors.lastname: Brandt
authors.forename: Terri A
authors.initials: TA
authors.lastname: Cummons
authors.forename: Diane
authors.initials: D
authors.lastname: Kowal
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Bojana
authors.initials: B
authors.lastname: Zupan
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Michael
authors.initials: M
authors.lastname: May
authors.forename: Cheryl
authors.initials: C
authors.lastname: Mugford
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kennedy
authors.forename: Wayne E
authors.initials: WE
authors.lastname: Childers
mesh_terms: D000284:Administration, Oral; D000818:Animals; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D004164:Diphosphonates / Q000138:chemical synthesis / Q000493:pharmacokinetics; D004355:Drug Stability; D005750:Gastric Juice / Q000378:metabolism; D008297:Male; D063065:Organophosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D053961:Azabicyclo Compounds; D004164:Diphosphonates; D063065:Organophosphonates; D011355:Prodrugs; D016194:Receptors, N-Methyl-D-Aspartate; C110623:EAA-090