title: Prodrug design, synthesis and pharmacokinetic evaluation of (3'R, 4'R)-3-hydroxymethyl-4-methyl-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone.
abstract: 3-Hydroxymethyl-4-methyl-DCK (3, HMDCK) was discovered previously as a potent HIV non-nucleoside reverse transcriptase inhibitor (NNRTIs) (EC50: 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 of3limits its further clinical development. In the current study, a series of ester prodrugs of3was designed and synthesized to explore the new drug candidates as NNRTIs. The l-alanine ester prodrug10exhibited desirable pharmacokinetic propertiesin vitroandin vivoand showed improved oral bioavailability of 26% in rat, and would be a potential clinical candidate as a new anti-AIDS drug.
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Huanfang
authors.initials: H
authors.lastname: Guo
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhuang
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.forename: Lianqi
authors.initials: L
authors.lastname: Sun
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Kuohsiung
authors.initials: K
authors.lastname: Lee
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
keywords: 3-Hydroxymethyl-4-methyl-DCK; Pharmacokinetic; Prodrug; Synthesis