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. 2012 Apr 1;2(2):213-219.
doi: 10.1016/j.apsb.2012.02.008.

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

Huanfang Guo  1 , Xiaomei Zhuang, Keduo Qian, Lianqi Sun, Xiaofeng Wang, Hua Li, Kuohsiung Lee, Lan Xie
Affiliations

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

Huanfang Guo et al. Acta Pharm Sin B. .

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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Figures

Figure 1
Figure 1
Structures of active DCK analogs.
Figure 2
Figure 2
In vitro metabolic stability in Sprague-Dawley rat liver microsomes of prodrugs and parent compound (3) as well as positive control drug propranolol (PRO).
Figure 3
Figure 3
Plasma concentration-versus-time curves of prodrugs and parent compound. (A) 3 with PEG400, i.v. administration at 2 mg/kg, and (B) prodrugs and 3 with PEG400, i.g. administration at 20 mg/kg. Results are averages of three independent assays.
Scheme 1
Scheme 1
Synthesis of prodrugs. (i) oxalyl chloride or suceinic anhydride, Py/CH2Cl22; (ii) sodium 2-ethylhexanoate/EtOAc; (iii) N-Boc-amino acid(s), Et3N/acetone; (iv) TFA/CH2Cl2; (v) HCl in diethyl ether.
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References

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