PHARMACOKINETICS AND METABOLISM OF EXP921, A NOVEL COGNITIVE ENHANCER, IN RATS

EXP921, nylmethyl)-5H-cyclopenta[2,1-b:3,4-b']-dipyridine, was a poten tial drug candidate for the improvement of cognitive performance in pa tients with Alzheimer's-type dementia, It has been shown to improve co gnitive performance in rodent and primate models of learning and memor y, To characterize the disposition of EXP921, the pharmacokinetics and metabolism of this compound were studied in rats after oral and intra venous 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 f rom 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 EXP991. This metabolite (EXP696) was rapidly formed, and si gnificant 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, demonstratin g that the N-oxidation at the pyridyl ring is reversible. The intercon version favored the oxidation of EXP921 to EXP696, Two additional meta bolites 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.