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Acta Pharm Sin B. 2012 Apr 1;2(2):213-219.

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

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  • 1Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.

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 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.

KEYWORDS:

3-Hydroxymethyl-4-methyl-DCK; Pharmacokinetic; Prodrug; Synthesis

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