Prodrug design, synthesis and pharmacokinetic evaluation of (3', 4')-3-hydroxymethyl-4-methyl-3',4'-di--()-camphanoyl-(+)--khellactone

ABSTRACT

3-Hydroxymethyl-4-methyl-DCK (, HMDCK) was discovered previously as a potent HIV non-nucleoside reverse transcriptase inhibitor (NNRTIs) (EC 0.004 μM, TI 6225) with a novel mechanism of action. It exerts anti-HIV activity by inhibiting the production of HIV-1 double-stranded viral DNA from a single-stranded DNA intermediate, rather than blocking the generation of single-stranded DNA from a RNA template, which is the mechanism of action of current HIV-1 RT inhibitors. However, the insufficient metabolic stability oflimits its further clinical development. In the current study, a series of ester prodrugs ofwas designed and synthesized to explore the new drug candidates as NNRTIs. The l-alanine ester prodrugexhibited desirable pharmacokinetic propertiesandand showed improved oral bioavailability of 26% in rat, and would be a potential clinical candidate as a new anti-AIDS drug.