Water-soluble prodrugs

To achieve high bioavailability of taxol, it needs to be highly soluble in water, but, in fact, it suffers from extremely low solubility in water ( 5 x 10 m). Thus, taxol 

In another approach, the C-2 position of taxol is the site of manipulation. Thus, a two-step enzymatic acylation in organic solvents has been employed to synthesize water-soluble taxol (paclitaxd) derivatives. In the first step, taxol 241 is reacted with the bifunctional acylating reagent 282, as catalyzed by thermolysin (from Bacillus thermoproteolyticus rokko), to give the activated acyl derivative 283. This is then used as a complex acyl donor in the second step [204]. 

The possibilities of detoxifying chemotherapeutics and of targeting drugs specifically to tumors have been investigated using taxol inclusion complexes with a cy-dodextrin dimer [205]. 

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SA Varia, S Schuller, KB Sloan, VJ Stella. Phenytoin prodrugs III Water-soluble prodrugs for oral and/or parenteral use. J Pharm Sci 73(8) 1068-1073, 1984. 

The methylprednisolone suleptanate 208b, the water-soluble prodrug of the methylprednisolone corticosteroid 208a, has been labelled with 14C exclusively at the carboxamide carbon175 which was found to be metabolically stable with no loss of 14CC>2 after administration to test animals and man. 

Y Hamada, J Ohtake, Y Sohma, T Kimura, Y Hayashi, Y Kiso. New water-soluble prodrugs of HIV protease inhibitors based on 0—>N intramolecular acyl migration. Bioorg Med Chem 10, 4155, 2002. 

N. L. Pochopin, W. N. Charman, V. J. Stella, Pharmacokinetics of Dapsone and Amino Acid Prodrugs of Dapsone , Drug Metab. Dispos. 1994, 22, 770-777 N. L. Pochopin, W. N. Charman, V. J. Stella, Amino Acid Derivatives of Dapsone as Water-Soluble Prodrugs , Int. J. Pharm. 1995, 121, 157-167. 

H. Bundgaard, C. Larsen, E. Arnold, Prodrugs as Drug Delivery Systems XXVII. Chemical Stability and Bioavailability of a Water-Soluble Prodrug of Metronidazole for Parenteral Administration , Int. J. Pharm. 1984, 18, 79-87. 

J. Takata, Y. Karube, M. Hanada, K. Matsunaga, Y. Matsushima, T. Sendo, T. Aoyama, Vitamin K Prodrugs 1. Synthesis of Amino Acid Esters of Menahydroquinone-4 and Enzymatic Reconversion to an Active Form , Pharm. Res. 1995, 12, 18-23 J. Takata, Y. Karube, M. Hanada, K. Matsunaga, Y. Matsushima, T. Sendo, R. Oishi, Vitamin K Prodrugs 2. Water-Soluble Prodrugs of Menahydroquinone-4 for Systemic Site-Specific Delivery , Pharm. Res. 1995, 12, 1973- 1979. 

H. Bundgaard, E. Falch, E. Jensen, A Novel Solution-Stable, Water-Soluble Prodrug Type for Drugs Containing a Hydroxyl or an NH-Acidic Group , J. Med. Chem. 1989, 32, 2503-2507. 

S. A. Varia, S. Schuller, K. B. Sloan, V. J. Stella, Phenytoin Prodrugs III Water-Soluble Prodrugs for Oral and/or Parenteral Use , J. Pharm. Sci. 1984, 73, 1068- 1073 S. A. Varia, S. Schuller, V. J. Stella, Phenytoin Prodrugs IV Hydrolysis of Various 3-(Hy-droxymethyl)phenytoin Esters , J. Pharm. Sci. 1984, 73, 1074-1080 S. A. Varia, V. J. Stella, Phenytoin Prodrugs V In vivo Evaluation of Some Water-Soluble Phenytoin Prodrugs in Dogs , J. Pharm. Sci. 1984, 73, 1080-1087. 

J. Leppanen, J. Huuskonen, J. Savolainen, T. Nevalainen, H. Taipale, J. Vepsalainen, J. Gynther, T. Jarvinen, Synthesis of a Water-Soluble Prodrug of Entacapone , Bioorg. Med. Chem. Lett. 2000, 10, 1967-1969 R. Sauer, J. Maurinsh, U. Reith, F. Ftille, K. N. Klotz, C. E. Muller, Water-Soluble Phosphate Prodrugs of l-Propargyl-8-styryl-xanthine Derivatives, A2A-Selective Adenosine Receptor Antagonists , J. Med. Chem. 2000, 43, 440-448. 

M. Safadi, R. Oliyai, V. J. Stella, Phosphoryloxymethyl Carbamates and Carbonates -Novel Water-Soluble Prodrugs for Amines and Hindered Alcohols , Pharm. Res. 1993, 10, 1350-1355. 

The URDP/PNP/Ara-U process is used to manufacture nelarabine, a water-soluble prodrug of 9-p-D-arabinofuranosylguanidine produced as a treatment for acute lymphoblastic leukaemia (Scheme 1.29). The two-enzyme process is run at 200 g... 

Tenofovir disopoxilfumarate is a water-soluble prodrug of active tenofovir. The oral bioavailability in fasted patients is approximately 25% and increases to 39% after a high-fat meal. The prolonged serum (12-17 hours) and intracellular half-lives allow once-daily dosing. Elimination occurs by both glomerular filtration and active tubular secretion. 

Stella, V.J, Lee, H.K, and Thompson, D.O. The effect of SfMBO on I.M. prednisolone pharmacokinetics and tissue damage in rabbits comparison to a co-solvent solution and a water-soluble prodrug,Int. J. Pharm, 120, 197-204, 1995. 

Ideally, a water-soluble prodrug product should have a shelf life of 2 years or more at room temperature, in which case the half-lifevitro should be at least 13 years. If the only purpose of prodrug formation is to improve the aqueous solubility of the parent compound, then bioconversion in vivo should be extremely rapid. If it is assumed that more than 90% of the prodrug is converted to the parent drug within 30 min of the injection, tlrevivo half-life should be 10 min or less. 

Ideal water-soluble prodrug design therefore requires aivo/in vitro lability ratio of nearly 1(f. 

Anderson, B. D., R. A. Conradi, and K. E. Knuth. 1985. Strategies in the design of solution-stable, water-soluble prodrugs. I. Aphysical-organic approach to pro-moiety selection for 21 -esters of corticosteroids. J. Pharm. Sci74 365-374. 

Bundgaard, H., C. Larsen, and E. Arnold. 1984a. Prodrugs as drug delivery systems. XXVII. Chemical stability and bioavailability of a water-soluble prodrug of metronidazole for parenteral administrated. 

Bundgaard, H., E. Falch, and E. Jensen. 1989. A novel solution-stable, water-soluble prodrug type for drugs containing a hydroxyl or an NH-acidic grou h.Med. Chem32 2503-2507. 

Cho, M. J., V. H. Sethy, and L. C. Haynes. 1986. Sequentially labile water-soluble prodrugs of alprazolam. 

Juntunen, J., J. Vepsalainen, R. Niemi, K. Laine, and T. Jarvinen. 2003. Synthesis evaluation, and intraocular pressure effects of water-soluble prodrugs of endocannabinoid noladid.dttef. Chem. 46 5083-5086. 

Lallemand, F., P. Perottet, O. Felt-Baeyens, W Kloeti, F. Philippoz, J. Marfurt, K. Besseghir, and R. Gurny. 2005b. A water-soluble prodrug of cyclosporine A for ocular application a stability study, J. 

Leppanen, J., J. Huuskonen, J. Savolainen, T. Nevalainen, H.Taipale, J. Vepsalainen, J. Gynther, andT. Jarvinen. 2000. Synthesis of a water-soluble prodrug of entacaffimorg. Med. Chem. LetllO 1967-1969. 

Mathew, A. E., M. R. Mejillano, J. P. Nath, R. H. Himes, andV. J. Stella. 1992. Synthesis and evaluation of some water-soluble prodrugs and derivatives of taxol with antitumor actiilitjdled. Chem35 145-151. 

Vermeersch, H., J. P. Remon, D. Permentier, and E. Schacht. ItSQfto antitrichomonal activity of water-soluble prodrug esters of metronidazdht J. Pharm.60 253-260. 

Zhao, Z., D. G. I. Kingston, andA. R. Crosswell. 1991. Moddtaxols. 6. Preparation of water soluble prodrugs of taxol. J. Nat. Prod.54 1607-1611. 

Furfine, E. S., Baker, C. T., Hale, M. R., Reynolds, D. J., Salisbury, J. A., Searle, A. D., Studenberg, S. D., Todd, D., Tung, R. D., and Spaltenstein, A. (2004). Preclinical pharmacology and pharmacokinetics of GW433908, a water-soluble prodrug of the human immunodeficiency virus protease inhibitor amprenavir. Antimicrob. Agents Chemother. 48 791-798. 

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