Prodrug design,synthesis and pharmacokinetic evaluation of(3'R,4'R)-3-hydroxymethyl-4-methyl-3',4'-di-O-(S)-camphanoyl-(t)-cis-khellactone

3-Hydroxymethyl-4-methyl-DCK(3,HMDCK)was discovered previously as a potent HIV non-nucleoside reverse transcriptase inhibitor(NNRTIs)(EC_(50):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 of 3 limits its further clinical development.In the current study,a series of ester prodrugs of 3 was designed and synthesized to explore the new drug candidates as NNRTIs.The L-alanine ester prodrug 10 exhibited desirable pharmacokinetic properties in vitro and in vivo and showed improved oral bioavailability of 26%in rat,and would be a potential clinical candidate as a new anti-AIDS drug.