Analogues and Prodrugs

In the course of drug design the two major types of chemical modifications are achieved through the formation of analogues and prodrugs. 

An analogue is normally accepted as being that modification which brings about a carbon-skeletal transformation or substituent synthesis. Examples oxytetracycline, demclocycline, chlortetracycline, trans-diethylstilbesterol with regard to oestradiol. 

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Differentiate the basic concepts of analogues" and prodrugs" with the help of suitable examples of parent drug molecule(s). 

The physiological activity of extracts from yew species has been known for millennia. In 1856, Lucas (358) isolated a mixture of alkaloids, which he called taxine and, 100 years later, Graf (359) showed this to be a mixture of at least seven compounds. Over 250 taxane diterpenoids are now known. Paclitaxel (312) was isolated from Taxus brevifolia (the Pacific Yew) in 1967 [360, 361] and its structure determined by X-ray crystallography in 1971 (362). The discovery of its anticancer properties led to a huge amount of research into its extraction, synthesis, production, and application. Bristol-Myers Squibb trademarked the name Taxol for paclitaxel and they, other pharmaceutical companies and academic researchers have invested much into the study of pacUtaxel and the search for active analogues and prodrugs. Some of the more significant materials in this series are shown in Fig. 8.59. 

Tenofovir disoproxil fumarate (Viread) is a prodrug of tenofovir, a phosphorylated adenosine nucleoside analogue, and is the only available agent of its class. It is converted by cellular enzymes to tenofovir diphosphate, which competes with deoxyadenosine triphosphate (dATP) for access to reverse transcriptase and causes chain termination following its incorporation. Tenofovir was approved as part of a combination therapy for HIV in adults who failed treatment with other regimens it appears to be effective against HIV strains that are resistant to NRTIs. The pharmacokinetic properties of tenofovir are provided in Table 51.2. 

Searcey et al. have just published additional work that supports an intercalative mode of binding, at least for partial azinomycin structures. They performed DNA unwinding assays with 77 and designed prodrug analogue 95 and conclude that both compounds bind weakly to DNA through intercalation [151],... 

Appropriately designed prodrugs, for example, phosphonoamidates (Lee et al. 2005), may allow acyclic nucleoside phosphonates such as tenofovir to be specifically targeted at tissues, that is, lymphatic tissue, where the virus (i.e., HIV) replicates. This principle has been recently extended to another nucleotide analogue, GS-9148 (Cmiar et al. 2008) and its phosphonoamidate prodrug, GS-9131 (Ray et al. 2008). 

GL Amidon, RS Pearlman, GD Lessman. In EB Roche, ed. Design of Biopharma-ceutical Properties Through Prodrugs and Analogues. Washington, DC American Pharmaceutical Association, 1977, pp 281-315. 

Thomsen, A. E., Friedrichsen, G., Sorensen, A. H., Andersen, R., Nielsen, C. U., Brodin, B., Begtrup, M., Frokjaer, S., Steffansen, B., Prodrugs of purine and pyrimidine analogues for the intestinal di/ tripeptide transporter PepTl affinity... 

S., Steffansen, B., Prodrugs of purine and pyrimidine analogues for oligopeptide transporter, AAPS Pharm. Sci. 2001, 3 suppl. 

The 3-formyl analogues of norfloxacin, pefloxacin and ciprofloxacin, (82a-c) have also been shown to function as prodrugs of their respective parent... 

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