Antimalarial pharmacodynamics and pharmacokinetics of a third-generation antifolate--JPC2056--in cynomolgus monkeys using an in vivo in vitro model.

OBJECTIVES: To assess the antimalarial pharmacodynamics and pharmacokinetics of the novel dihydrofolate reductase (DHFR) inhibitor, JPC2056 and its principal active metabolite JPC2067 in cynomolgus monkeys using an in vivo-in vitro model. METHODS: In a two-phase crossover design, five cynomolgus monkeys were administered a single dose (20 mg/kg) and multiple doses (20 mg/kg daily for 3 days) of JPC2056. Plasma samples collected from treated monkeys were assessed for in vitro antimalarial activity against Plasmodium falciparum lines having wild-type (D6), double-mutant (K1) and quadruple-mutant (TM90-C2A) DHFR-thymidylate synthase (TS) and a P. falciparum line transformed with a Plasmodium vivax dhfr-ts quadruple-mutant allele (D6-PvDHFR). Plasma JPC2056 and JPC2067 concentrations were measured by LC-mass spectrometry. RESULTS: The mean inhibitory dilution (ID(90)) of monkey plasma at 3 h after drug administration against D6, K1 and TM90-C2A was, respectively, 1253, 585 and 869 after the single-dose regimen and 1613, 1120 and 1396 following the multiple-dose regimen. Less activity was observed with the same monkey plasma samples against the D6-PvDHFR line, with a mean ID(90) of 53 after multiple dosing. Geometric mean plasma concentrations of JPC2056 and JPC2067 at 3 h after drug administration were, respectively, 113 and 12 ng/mL after the single dose and 150 and 17 ng/mL after multiple dosing. The mean elimination half-life of JPC2056 was shorter than its metabolite after both regimens (single dose, 7.3 versus 11.8 h; multiple doses, 6.6 versus 11.1 h). CONCLUSIONS: The high potency of JPC2056 against P. falciparum DHFR-TS quadruple-mutant lines provides optimism for the future development of JPC2056 for the treatment of malaria infections.

In vitro and in vivo efficacy and in vitro metabolism of 1-phenyl-3-aryl-2-propen-1-ones against Plasmodium falciparum.

Investigation of a series of 1-phenyl-3-aryl-2-propen-1-ones resulted in the identification of nine inhibitors with submicromolar efficacy against at least one Plasmodium falciparum strain in vitro. These inhibitors were inactive when given orally in a Plasmodium berghei infected mouse model. Significant compound degradation occurred upon their exposure to a liver microsome preparation, suggesting metabolic instability may be responsible for the lack of activity in vivo.

Structure identification and prophylactic antimalarial efficacy of 2-guanidinoimidazolidinedione derivatives.

The reported synthetic procedure of WR182393, a 2-guanidinoimidazolidinedione derivative with high prophylactic antimalarial activity, was found to be a mixture of three closely related products. Poor solubility of WR182393 in both water and organic solvents and its impractical synthetic method have made the purification and structure identification of the reaction mixture a highly challenging task. The problems were circumvented by prodrug approach involving carbamate formation of the mixture, which enhances the solubility of the mixture in common organic solvents and facilitates the separation and structure determination of the two products. The structures of the two components were determined by X-ray crystallography and NMR of their corresponding carbamates 3a and 4a. Additional alkyl carbamates were prepared according to the same approach and two new carbamates 3b and 4d were found to possess higher intramuscular (im) efficacy than the parent compound WR182393 against Plasmodium cynomolgi in Rhesus monkey.

Synthesis of tetrasubstituted ozonides by the Griesbaum coozonolysis reaction: diastereoselectivity and functional group transformations by post-ozonolysis reactions.

The diastereoselectivity of the Griesbaum coozonolysis reaction with O-methyl 2-adamantanone oxime and 4-substituted cyclohexanones reveals that the major tetrasubstituted ozonide isomers possess cis configurations, suggesting a preferred axial attack of the carbonyl oxide on the cyclohexanone dipolarophiles. It is evident that these tetrasubstituted ozonides are quite stable to triphenylphosphine, borohydrides, hydrazine, alkyllithiums, Grignard reagents, mercaptides, and aqueous KOH as illustrated by the synthesis of amine, alcohol, acid, ester, ether, sulfide, sulfone, and heterocycle-functionalized ozonides by a wide range of post-ozonolysis transformations.