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A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.

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2-Deoxy-3-thiacytidine is a dideoxycytidine analog with a sulfur in place of the 3 carbon of the ribose. There are two enantiomeric forms of the compound, both of which inhibit human immunodeficiency virus type 1 and 2 replication in vitro. However, the (؊) enantiomer (lamivudine) appears to be significantly less cytotoxic to uninfected lymphocytes than is the (؉) enantiomer. Lamivudine has entered initial clinical trials, and the present study was designed to describe the pharmacokinetic behavior of this compound in both plasma and cerebrospinal fluid (CSF) of primates. Lamivudine was administered as an intravenous bolus dose of 20 mg/kg to five nonhuman primates, and plasma and CSF (ventricular and lumbar) were sampled at frequent intervals for 24 h after administration. Urine samples were also obtained from two animals. The same dose of the racemate (BCH-189) was administered to one animal. The drug was quantitated in CSF and plasma with a reverse-phase high-pressure liquid chromatography technique. Elimination of lamivudine from plasma was biexponential, with a mean alpha phase half-life of 5.4 min, a mean beta phase half-life of 84 min, and a total clearance of 6.1 liters/h. The total clearance of the same dose of BCH-189 in a single animal was 11.0 liters/h. In two animals from which urine was obtained for 12 h postadministration, 32 and 59% of the drug was recovered unchanged. The deamination product of lamivudine was not detected. The CSF/plasma ratio of lamivudine was significantly higher when the drug was measured in the lumbar CSF (mean, 0.41) than when it was measured in the ventricular CSF (mean, 0.079). The measured CSF/plasma ratio for ventricular CSF is equivalent to that of other dideoxycytidine analogs, confirming the importance of the nucleobase in determining the degree of CSF penetration. The difference in lamivudine exposure in ventricular and lumbar CSF suggests that there is a transport mechanism for efflux of cytidine analogs from ventricular CSF.Lamivudine, the (Ϫ) enantiomer of 2Ј-deoxy-3Ј-thiacytidine, is a dideoxynucleoside analog in which the 3Ј carbon of the ribose of 2Ј,3Ј-dideoxycytidine (ddC) is replaced by a sulfur (Fig. 1). (1). Both the (Ϫ) and (ϩ) enantiomers of 2Ј-deoxy-3Ј-thiacytidine have been shown to inhibit in vitro replication of human immunodeficiency virus types 1 and 2. However, in preclinical studies lamivudine appeared to be significantly less cytotoxic to uninfected lymphocytes than did the (ϩ) enantiomer (3). On the basis of the in vitro antiretroviral activity and the relative lack of cytotoxicity of lamivudine, phase I/II clinical trials of this agent with both children and adults have been initiated (5,9,12,16).The cerebrospinal fluid (CSF) penetration of several other pyrimidine dideoxynucleosides, including zidovudine and ddC, has been studied in a nonhuman primate model. These studies suggest that the degree of CSF penetration is dependent upon the nucleobase rather than the structural changes to the sugar moiety. In the present study, the plasma and CSF ...