Prodrugs

Prodrugs are compounds which may be inactive in themselves, but which can be converted by chemical or enzymatic means to an active drug. They have been useful 

N-Demethylation is a common metabolic reaction in the liver. Therefore, primary or secondary amines could be N-methylated to improve their membrane permeability. Several hypnotics and antiepileptics take advantage of this reaction (e.g. hexobarbitone (Fig. 8.12)). 

Another way round the problem of membrane permeability is to design a prodrug which can take advantage of a carrier protein in the cell membrane, such as the one responsible for carrying amino acids into a cell. The best known example of such a prodrug is levodopa (Fig. 8.13). 

Levodopa is a prodrug for the neurotransmitter dopamine and as such has been used in the treatment of Parkinson s disease—a condition due primarily to a deficiency of the neurotransmitter dopamine. Dopamine itself cannot be used since it is too polar to cross the blood-brain barrier. 

Levodopa is even more polar and seems an unlikely prodrug. However, it is an amino acid and as such can make use of the special arrangements made in order to move amino acids across the blood-brain barrier. Amino acids are essential building blocks for all cells, but are incapable of crossing hydrophobic membranes by themselves. There is, however, a process by which amino acids can be shuttled through membranes such as the blood-brain barrier. This 

In the case of incomplete degradation resulting in the formation of dead-end products, the situation may be worse, as we have little or no knowledge on the biological activity and environmental fate of these dead-end transformation products. 

105 is in equilibrium with aldocyclophosphamide (8.106). In tumor cells, 8.106 undergoes an elimination to yield acrolein (8.107) and phosphoramide (8.108). Phosphoramide is the active metabolite. The low oral bioavailability of phosphoramide necessitates the use of the more orally available cyclophosphamide (F — 75% ).24 

The following Case Study demonstrates the challenges that administration of a prodrug can pose to a drug discovery program. 

Clopidogrel has been found to be ineffective for certain segments of the population. Between 2% and 14% of the population in the United States has been estimated 

Because prasugrel is activated by lipases that show essentially no reaction variability across different populations, prasugrel displays a more uniform level of activity than CYP2C 19-dependent clopidogrel. The more predictable behavior of prasugrel allows it to avoid the undesirable black box warning carried by clopidogrel. 

The following figures represent dextromethorphan (8.a) and several of its known metabolites dextrorphan (8.b) (primary metabolite), dextrorphan O-sulfate (8.c), and 3-hydroxymor-phinan (8.d). List the different reactions (in their likely order) that dextromethorphan underwent to form each metabolite. 

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Interest contmues in prodrugs of 5-fluorouracil (5-FU) Doxifluridine (8) was recently mtroduced and appears to be more potent and less toxic than 5 FU [10 Flutamide (9) and nilutamide (/O) are both available for the treatment of prostatic cancer [//, 12]... 

The anticonvulsant progabide 24) is useful in a wide variety of seizure disorders. It was synthesiied as a y-aniinobutync acid (GABA) prodrug but its activity appears to reside in the parent drug and its acid metabolite, as well as the GABA liberated [21],... 

Lethal drug interactions of new antiviral, sorivudin [l-(3-D-arabinofuranosyl-( )-5-(2-bromvinyl)uracil], with anticancer prodrugs of 5-fluorouracil structure 97YZ910. 

One of the first prodrugs, aspirin, is cleaved to the active agent, salcylic acid, in the liver as well as various other tissues. Despite the advent of numerous newer agents for the alleviation of the pain and inflammation characteristic of inflammatory diseases, aspirin remains the most widely used drug for this 108... 

An alternate route to ampicillin not only circumvents the need for 6-APA but also has the advantage of providing a prodrug form of ampicillin as well as the parent compound. Reaction of benzylpenicillin (4) with the acid protecting group, 29, gives the formol ester, 30. Reaction of the product with phosphorus pentachloride leads to the corresponding imino chloride (31). 

Latentiation of ampicillin can also be achieved by tying up the proximate amino and amide functions as an acetone aminal. Inclusion of acetone in the reaction mixture allows 6-APA to be condensed directly with the acid chloride from 24. There is thus obtained directly the prodrug hetacillin (34). Although this compound has little antibiotic activity in its own right, it hydrolyzes to ampicillin in the body. The p-hydroxy derivative amoxycillin (35) shows somewhat better oral activity. A similar sequence using formaldehyde gives metampicillin (36). °... 

Prodrug. A precursor that, after administration and subsequent transformation in the body, forms the active drug. 

Preparation of the first of these antiinflammatory prodrugs starts with the displacement of halogen on bromophthal ide 2 by the anion of the nicotinic acid derivative 1. Reaction of the intermediate 3 with aniline 4 leads to formation of talniflumate (5). ... 

It is quickly deacylated in vivo and may qualify as a prodrug. The published synthesis is rather long and bears conceptual similarities to the synthesis of cannabinoids. It has some five asymmetric centers. Dane salt formation between 3,5-di-methoxyani1ine and ethyl acetoacetate followed by borohydride reduction gives synthon The amino group is protected by... 

Sarpicillin (10) is a double prodrug of ampicillin in that not only is the carboxy group masked as an ester, but a... 

Viprostol (81) also incorporates a hydroxy group moved to C-16 and protects this from facile metabolic oxidation by vinylation. It is a potent hypotensive and vasodilatory agent both orally and transdermally. The methyl ester moiety is rapidly hydrolyzed in skin and in the liver so it is essentially a prodrug. It is synthesized from protected E-iodo olefin 78 (compare with 75) by conversion to the mixed organocuprate and this added in a 1,4-sense to olefin 79 to produce protected intermediate 80. The synthesis of viprostol concludes by deblocking with acetic acid and then reesterification with diazomethane to give 81 [19]. 

It has been shown that glyeine amides of aminobenzophenones are readily converted to the corresponding benzodiazepines in vivo. Peptides which terminate in such a moiety should thus serve as a benzodiazepine prodrug after hydrolysis by peptidases. One of the glycine residues in lorzafone (194)is presumably removed metabolicaUy in this manner to give a benzodiazepine precursor which spontaneously cyclizes. Acylation of benzophenone 190 with the trityl protected dipeptide 191, as its acid chloride 192, affords the amide 193. Removal of the trityl protecting group with acid yields lorzafone (194) [50]. 

One of the problems with cycloserine (57) as an antibacterial agent is its tendency to dimenze In an attempt to overcome this, the prodrug penti/idone (59) has been prepared The primary amino group essential for the dimenzation reacnon is reversibly blocked to prevent this Penti/idone is synthesized conveniently from cycloserine (57) by merely mixing it with acetyl acetone (58) and storing for two days to achieve the dehydration The resulting pentizidone apparently requires enzymic assistance to release cycloserine in vivo [20]... 

In order to enhance the oral bioavailability of oximonam (104), a prodrug has been made by esterification of the carboxyl group with the t-butyl ester of hydroxyacetic acid (105). The product is prodrug gloximonam (106) [31], Gloximonam is efficiently converted to oximonam in the body by metabolic processes. 

As well as complex biological targets, complex chemical targets (drugs with multiple activity, prodrugs) can be used to produce therapeutically useful phenotypic responses. 

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],... 

Most ACE inhibitors are prodrugs, with the exceptions of captopril, lisinopril, and ceranapril. Prodrugs exert improved oral bioavailability, but need to be converted to active compounds in the liver, kidney, and/or intestinal tract. In effect, converting enzyme inhibitors have quite different kinetic profiles with regard to half time, onset and duration of action, or tissue penetration. 

Although the 3 - and 5 -polyphosphate derivatives mentioned above exhibit exquisite inhibitory potency these compounds are not cell permeable. To take advantage ofthepotency of such derivatives for studies with intact cells and tissues, there are two possibilities. One is chemically to protect the phosphate groups from exonucleotidases that also allows the compound to transit the membrane intact. The other is to provide a precursor molecule that is cell permeable and is then metabolized into an inhibitor by intracellular enzymes. The general term for such a compound is prodrug nucleotide precursors are also referred to as pronucleotides. Families of protected monophosphate derivatives were synthesized, based on (3-L- and 3-D-2, 5 -dd-3 -AMP, 3-L-2, 3 -dd-5 -AMP, and the acyclic 9-substituted adenines, PMEA and PMPA. Protective substituents were (i) -( -pivaloyl-2-thioethyl) ... 

Adenylyl Cyclases. Table 5 Prodrug inhibition of [3H] cAMP formation in intact cells. Cells were prelabeled for 2 h with [3H]adenine before 50 pM forskolin and pronucleotides were added. After a 15 min incubation the newly formed [3H]cAMP was extracted and quantified as in (7)... 

Ajmaline (intravenously only) and its orally applicable propyl-substituted prodrug prajmaline are classified as class IA drugs, but due to their long dissociation time constant can also be considered as class IC compounds. 

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