Prodrugs approach

Other patent reports covering PDF inhibitors from structural classes different from those discussed above include hydrazides (43) [118], aryl-substituted pyrrolidines (44) [119], benzimidazoles (45, 46) [120-121], hydantoins (47) [122] and oxo-pyrrolidines (48) [123], A prodrug approach utilising PDF has been published by Pei, and patents have been published by NewBiotics, but in this case the compounds of interest are used as substrates rather than inhibitors (49) [124-126]. 

The most serious disadvantage of the prodrug approach to controlled sustained delivery is that extensive development must be undertaken to find the correct chemical modification for a specific drug. Additionally, once a prodrug is formed, it is a new drug entity and, therefore, requires extensive and costly studies to determine safety and efficacy. 

A prodrug approach may be used to obtain maximum systemic concentration in the body by the oral route. The prodrug optimization of drug delivery may overcome several limiting factors such as... 

Prodrug approaches have been used to increase the oral bioavailabilities of cephalosporins. Ester prodrugs are formed by reversible esterification of the carboxyl group on these antibiotics [20], These prodrugs are more orally bio-... 

Overall, the prodrug approach is a well-established strategy to improve the bioavailability and targeting of pharmacophores, and is a vital component in the development of therapeutics and drug-delivery strategies. 

Golomb, G., A peptide prodrug approach for improving bisphos-phonate oral absorption, J. Med. 

Figure 18.5 Alcohol containing VEGFR-2 inhibitor used for a prodrug approach.

In recent years, significant progress has been made in developing prodrug approaches to improve the water solubility, membrane permeability, in vivo distribution, and stability of peptides [193-197]. 

A. Ezra, A. Hoffman, E. Breuer, I. S. Alferiev, J. Monkkonen, N. El Hanany-Rozen, G. Weiss, D. Stepensky, I. Gati, H. Cohen, S. Tormalehto, G. L. Amidon, G. Golomb, A Peptide Prodrug Approach for Improving Bisphosphonate Oral Absorption , J. Med. Chem. 2000, 43, 3641-3652. 

W. Wang, J. Jiang, C. E. Ballard, B. Wang, Prodrug Approaches to the Improved Delivery of Peptide Drugs , Curr. Pharm. Design 1999, 5, 265 - 287. 

Phosphoramidates are organophosphorus compounds containing a P-N bond. In recent years, innovative prodrug approaches have been developed based on the cleavage of the P-N bond, two examples of which are presented here. 

J. Patel, M. J. Katovich, K. B. Sloan, S. H. Curry, R. J. Prankerd, A Prodrug Approach to Increasing the Oral Potency of a Phenolic Drug. Part 2. Pharmacodynamics and Preliminary Bioavailabihty of an Orally Administered O-(Imidomethyl) Derivative of 17/3-Estradiol , J. Pharm. Sci. 1995, 84, 174- 178. 

Despite excellent intrinsic potency, weak oral activity limited the in vivo activity of 218 d. Efforts to improve its oral bioavailability by a prodrug approach led to the preparation of two compounds with improved oral activity and bioavailability, the dioxolenonylmethanol ester BMS 184698 219 and the M-alkyl tetrazole prodrug 220, Eq. (88). 

A. A. Sinkula (1975). Prodrug approach in drug design. Annu. Rep. Med. Chem. 10 306-316. 

Krise, J. P. 1999. Novel prodrug approach for tertiary amines synthesis and preliminary evaluation of N-phosphonooxymethyl prodrugi.Med. Chem42 3094-3100. 

Krise, J. P, S. Narisawa, and V. J. Stella. 1999a. A novel prodrug approach for tertiary amines. 2. Physicochemical andn vitro enzymatic evaluation of selectettphosphonooxymethyl prodrugi. Pharm. 

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