RT Journal Article
SR Electronic
T1 Pharmacokinetics and metabolism of EXP921, a novel cognitive enhancer, in rats.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 172
OP 179
VO 24
IS 2
A1 Y N Wong
A1 C Y Quon
A1 K A Holm
A1 D L Burcham
A1 N L Frey
A1 S M Huang
A1 G N Lam
YR 1996
UL http://dmd.aspetjournals.org/content/24/2/172.abstract
AB EXP921, 5,5-bis(4-pyridinylmethyl)-5H-cyclopenta[2,1-b:3,4-b']-dipyridine, was a potential drug candidate for the improvement of cognitive performance in patients with Alzheimer's-type dementia. It has been shown to improve cognitive performance in rodent and primate models of learning and memory. To characterize the disposition of EXP921, the pharmacokinetics and metabolism of this compound were studied in rats after oral and intravenous administrations. EXP921 exhibited good bioavailability, 43% at 3 mg/kg and 61% at 10 mg/kg and was rapidly eliminated with a terminal half-life ranging from 1.28 to 2.29 hr after oral doses. Absorption from oral doses was rapid, as peak plasma levels were reached within 1 hr. A major metabolite was identified in plasma as the pyridinyl mono-N-oxide of EXP921. This metabolite (EXP696) was rapidly formed, and significant levels were detected in rat plasma after oral or intravenous administration. Its terminal half-life was slightly longer than that of EXP921. EXP696 was found to be reduced back to EXP921, demonstrating that the N-oxidation at the pyridyl ring is reversible. The interconversion favored the oxidation of EXP921 to EXP696. Two additional metabolites were identified in rat plasma at doses higher than or equal to 30 mg/kg. They result from despicolylation, followed by hydroxylation in the cyclopentane ring.