Prodrug design, synthesis and pharmacokinetic evaluation of (3', 4')-3-hydroxymethyl-4-methyl-3',4'-di--()-camphanoyl-(+)--khellactone.
- Author:
Huanfang GUO
1
;
Xiaomei ZHUANG
;
Keduo QIAN
;
Lianqi SUN
;
Xiaofeng WANG
;
Hua LI
;
Kuohsiung LEE
;
Lan XIE
Author Information
1. Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
- Publication Type:Journal Article
- Keywords:
3-Hydroxymethyl-4-methyl-DCK;
Pharmacokinetic;
Prodrug;
Synthesis
- From:
Acta Pharmaceutica Sinica B
2012;2(2):213-219
- CountryChina
- Language:English
-
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.
