Prodrugs of perzinfotel with improved oral bioavailability.
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.
Baudy
Reinhardt B
RB
Chemical & Screening Sciences, Wyeth Research, CN-8000, Princeton, New Jersey 08543, USA.
Butera
John A
JA
Abou-Gharbia
Magid A
MA
Chen
Hong
H
Harrison
Boyd
B
Jain
Uday
U
Magolda
Ronald
R
Sze
Jean Y
JY
Brandt
Michael R
MR
Cummons
Terri A
TA
Kowal
Diane
D
Pangalos
Menelas N
MN
Zupan
Bojana
B
Hoffmann
Matthew
M
May
Michael
M
Mugford
Cheryl
C
Kennedy
Jeffrey
J
Childers
Wayne E
WE
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
D053961:Azabicyclo Compounds; D004164:Diphosphonates; D063065:Organophosphonates; D011355:Prodrugs; D016194:Receptors, N-Methyl-D-Aspartate; C110623:EAA-090