Nipecotic Acid Synthesis Essay

3

Derivatization of Drugs Containing a Carboxylic Acid Functional Group

Lipophilic prodrugs can also be derived from a carboxylic functional group, the most commonly used derivatives being carboxylic esters. Simple esters of aliphatic alcohols are attractive, as they are cheap to prepare, chemically stable, and yield harmless hydrolysis products [47]. Typical representatives of such prodrugs are tyrosine methyl ester [48], levodopa ethyl ester [49], nipecotic acid ethyl ester [50], enalaprilat ethyl ester [51,52], trandolapril [53], γ-aminobutyric acid (GABA) cetyl ester [54,55], and methotrexate cetyl ester [56].

Lipoidal prodrugs, in which the carboxyl function esterifies the free alcoholic hydroxyl of 1,2- or 1,3-diglyceride, are well absorbed and show high lymphotropism [57,58]. Due to their greasy properties and difficult purification, these compounds have limited industrial application.

The widespread use of acyloxymethyl esters in antibiotic chemistry, as illustrated above for bacampicillin, was initiated by Jansen and Russel [59] at Wyeth Laboratories and successfully applied to pivampicillin [14], talampicillin [16], and cephalosporins [60]. In each of these cases, the oral absorption of the antibiotic was improved by some 2–3-fold over that of the parent compound. The acyloxymethyl derivatization was also extended to amino acids such as α-methyldopa [61], isoguvacine [62], or tranexamic acid [63], to anti-inflammatory drugs such as niflumic acid [64] or indomethacin [65], and to quinolone antibacterials such as norfloxacin [66].

Mixed anhydrides represent original attempts to prepare prodrugs of carboxylic or phosphonic acids [67]. Clodronic acid dianhydrides (Figure 28.9), for example, were shown to be novel bioreversible prodrugs of clodronate. They are more lipophilic than the parent clodronate, stable against chemical hydrolysis, and hydrolyze enzymatically to clodronate in human serum [68].

A novel prodrug class introduced by P&G researchers to increase lipophilicity (absorption) and reduce food effects hypothesized to be caused by Ca++2 complexation of bisphosphonic acid groups comprises the cyclic acetal prodrugs. Intraduodenal administration of the prodrug (Figure 28.10) to fed rats resulted in greater risedronate exposure compared to dosing risedronate based on urinary recovery [69]. Systemic rate of conversion of the cyclic acetal to risedronate can be modulated by substitution on the phenyl ring. Preliminary experimental studies suggested that oral administration of bisphosphonate cyclic acetals can improve bisphosphonate exposure even under fed conditions, as long as these prodrugs are stable enough in the stomach to ensure premature release of parent drug does not occur.

In contrast to modifications on the bisphosphonate side chain described earlier, Medivir scientists incorporated distil PepT1 recognition elements to the phosphonic acid moiety to mask the highly ionized functionality and promote carrier-mediated transport [70]. Absolute bioavailability (BA) was determined as the ratio of the area under the curves (AUCs) of the prodrug administered orally against the parent drug administered i.v., and the most promising examples are shown in Figure 28.11. These data suggest significant enhanced oral bioavailability of these prodrugs relative to alendronate. The efficiency of bioconversion, however, is not described.

Methoxy-imino bioisosteres of carboxylic acid anhydrides, which can be prepared by O-acylation of the corresponding hydroxamates, represent another way to prepare prodrugs of carboxylic acids (Figure 28.12). One of these derivatives, compound FOX 988, a diabetes drug, was designed as a prodrug of 4-(2,2-dimethyl-1-hydroxypropyl) benzoic acid. In the liver this prodrug is metabolized at a rate sufficient to possess hypoglycemic potency (an ED50 of 65 µmol/kg, 28 mg/kg/day, for glucose lowering) [71] but avoids significant release of the active metabolite to the systemic circulation to avoid testicular toxicity at doses up to 1,500 µmol/kg/day. The mechanism of action of 4-(2,2-dimethyl-1-hydroxypropyl) benzoic acid is the sequestration of coenzyme A (CoA) in the mitochondria, thus inhibiting medium-chain acyltransferase and, as a consequence, causing hepatic neoglucogenesis [72].

Primary amides of carboxylic acids are easily converted in humans to the corresponding acid (e.g., depamide, progabide) by amidases and can thus be used in prodrug design. Amides of ketoprofen-derived arylacetic acids possess a therapeutic index one order of magnitude greater than that of indomethacin [73].

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