Application of the 'trimethyl lock' to Ganciclovir, a pro-prodrug with increased oral bioavailability

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 14, 1996, Pages 1653-1656

  Dillon, Michael P ^a   Cai, Haiying ^a   Maag, Hans ^a  

^a ROCHE BIOSCIENCE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ESTER; GANCICLOVIR; GANCICLOVIR DERIVATIVE; PRODRUG;

ANIMAL EXPERIMENT; ARTICLE; BIOAVAILABILITY; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG DESIGN; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; MALE; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT; ULTRAVIOLET SPECTROPHOTOMETRY;

ANIMALIA;

EID: 0030598672     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00294-6     Document Type: Article

References (17)

1. 1. 3-(2'-Hydroxy-4'6'-dimethylphenyl)-3,3-dimethylpropanoic acid derivatives; see Amsberry, K. L.; Borchardt, R. T. J. Org. Chem. 1990, 55, 5867, and references cited therein.
2. 2. Contribitution No. 939 from Chemical Research and Development.
3. 3. Present address: Roche Bioscience, 3401 Hillview Avenue, Palo Alto, CA 94304.
4. 4. Bundgaard, H. Drugs Future 1991, 76, 443.
5. 5. Design of Prodrugs; Bundgaard, H., Ed.; Elsevier: Amsterdam 1985.
6. 6. Stella, V. J.; Charman, W. N. A.; Naringrekar, V. H. Drugs 1985, 29, 455.
7. 7. Bundgaard, H. Adv. Drug Deliv. Rev. 1989, 3, 39.
8. 8. 9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine, also known as DHPG; Martin, J. C.; Dvorak, C. A.; Smee, D. F.; Matthews, T. R.; Verheyden, J. P. H. J. Med. Chem. 1983, 26, 759.
9. 9. Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roszkowski, A.; Tomolonis, A.; Fried, J. J. Med. Chem. 1970, 13, 203.
10. 10. Ferres, H. Drugs Today 1983, 19, 499.
11. 11. Amsberry, K. L.; Gerstenberger, A. E.; Borchardt, R. T. Pharm. Res. 1991, 8, 455.
12. 12. In our hands conversion of the 3-(2'-acetoxy-4'6'-dimethylphenyl)-3,3-dimethyl propanol into the corresponding acid was best achieved by initial oxidation under Swern conditions followed by a second oxidation with sodium chlorite in the presence of 2-methyl-2-butene. Oxidation of 3-(2'-benzyloxy-4'6'-dimethylphenyl)-3,3-dimethyl propanol into the corresponding acid was accomplished is one step using potassium dichromate.
13. 13. Martin, J. C.; Tippie, M. A.; McGee, D. P. C.; Verheyden, J. P. H. J. Pharm. Sci. 1987, 76, 180.
14. 14. All new compounds gave spectral and analytical data consistent with their assigned structures.
15. 15. To measure oral bioavailability, the plasma levels of Ganciclovir were determined in male rats at ten time points (15 min to 24 h) after a single oral dose (po) of either Ganciclovir or the pro-prodrug of Ganciclovir, respectively. A colony of 40 rats were dosed initially, 4 rats were removed at each time point and the bioavailability determined. For Ganciclovir the oral dose was 10 mg/kg, for the pro-prodrug esters the dose in each case was equimolar to 10 mg/kg of Ganciclovir. The dose vehicle for the oral dose consisted of 0.5% carboxymethyl cellulose, 0.4% polysorbate alcohol, 0.9% benzyl alcohol and 0.9% NaCl with the pH adjusted to 3.5 with HCl (rest water). The plasma levels of Ganciclovir obtained after oral administration of Ganciclovir or the pro-prodrug of Ganciclovir were compared with the plasma levels obtained after an iv administration of an equimolar amount of Ganciclovir (10 mg/kg) utilizing the area under the curve of the plasma concentration vs. time plot over a 24 h period following dosing. For iv administration the sodium salt of Ganciclovir was formulated in normal saline solution. Aliquots of plasma were analyzed by HPLC where Ganciclovir and an internal standard were detected by UV absorbency at 254 nm.
16. 16. At each time point, one concentration was drawn at random form the observed values and an area under the curve calculated, this procedure was repeated 1000 times.
17. 17. Dillon, M. P.; Cai, H.; Maag, H. manuscript in preparation.